bims-meract 2025-01-12 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2025–01–12
25 papers selected by
Andrea Morandi, Università degli Studi di Firenze

FOXC1-mediated serine metabolism reprogramming enhances colorectal cancer growth and 5-FU resistance under serine restriction.
CD36 as a Therapeutic Target in Tumor Microenvironment and Lipid Metabolism.
YY2-CYP51A1 signaling suppresses hepatocellular carcinoma progression by restraining de novo cholesterol biosynthesis.
Oxidative Phosphorylation is a Metabolic Vulnerability of Endocrine Therapy-Tolerant Persister Cells in ER+ Breast Cancer.
Metabolic Switch in Endocrine Resistant Estrogen Receptor Positive Breast Cancer.
S100P is a ferroptosis suppressor to facilitate hepatocellular carcinoma development by rewiring lipid metabolism.
De novo lipogenesis protects dormant breast cancer cells from ferroptosis and promotes metastasis.
Inosine monophosphate dehydrogenase 2 (IMPDH2) modulates response to therapy and chemo-resistance in triple negative breast cancer.
Metabolic reprogramming induced by PSMA4 overexpression facilitates bortezomib resistance in multiple myeloma.
The role of mitochondrial dysfunction in the cytotoxic synergistic effect of gemcitabine and arsenic on breast cancer.
FASN inhibition shows the potential for enhancing radiotherapy outcomes by targeting glycolysis, AKT, and ERK pathways in breast cancer.
Targeting ferroptosis: a promising strategy to overcome drug resistance in breast cancer.
Amitriptyline revitalizes ICB response via dually inhibiting Kyn/Indole and 5-HT pathways of tryptophan metabolism in ovarian cancer.
ONC213: a novel strategy to resensitize resistant AML cells to venetoclax through induction of mitochondrial stress.
The histone lactylation of AIM2 influences the suppression of ferroptosis by ACSL4 through STAT5B and promotes the progression of lung cancer.
Strategies to Overcome Intrinsic and Acquired Resistance to Chemoradiotherapy in Head and Neck Cancer.
Statins inhibit onco-dimerization of the 4Ig isoform of B7-H3.
Seryl-tRNA synthetase inhibits Wnt signaling and breast cancer progression and metastasis.
HDAC inhibitor enhances ferroptosis susceptibility of AML cells by stimulating iron metabolism.
Dual-template epitope imprinted nanoparticles for anti-glycolytic tumor-targeted treatment.
Mitochondria: a crucial factor in the progression and drug resistance of colorectal cancer.
NXP800 activates the unfolded protein response, altering AR and E2F function to impact castration-resistant prostate cancer growth.
Pharmacological Inhibition of Astrocytic Transglutaminase 2 Facilitates the Expression of a Neurosupportive Astrocyte Reactive Phenotype in Association with Increased Histone Acetylation.
α-Ketoglutarate dehydrogenase is a therapeutic vulnerability in acute myeloid leukemia.
Targeting Siglec-15 mediates mitochondrial retrograde regulation of cervical cancer development.

Cell Commun Signal. 2025 Jan 07. 23(1): 13

FOXC1-mediated serine metabolism reprogramming enhances colorectal cancer growth and 5-FU resistance under serine restriction.

Zhukai Chen, Jiacheng Xu, Kang Fang, Hanyu Jiang, Zhuyun Leng, Hao Wu, Zehua Zhang, Zeyu Wang, Zhaoxing Li, Mingchuang Sun, Ziying Zhao, Anqi Feng, Shihan Zhang, Yuan Chu, Lechi Ye, Meidong Xu, Lingnan He, Tao Chen.

  Colorectal cancer (CRC) is the most common gastrointestinal malignancy, and 5-Fluorouracil (5-FU) is the principal chemotherapeutic drug used for its treatment. However, 5-FU resistance remains a significant challenge. Under stress conditions, tumor metabolic reprogramming influences 5-FU resistance. Serine metabolism plasticity is one of the crucial metabolic pathways influencing 5-FU resistance in CRC. However, the mechanisms by which CRC modulates serine metabolic reprogramming under serine-deprived conditions remain unknown. We found that exogenous serine deprivation enhanced the expression of serine synthesis pathway (SSP) genes, which in turn supported CRC cell growth and 5-FU resistance. Serine deprivation activate the ERK1/2-p-ELK1 signaling axis, leading to upregulated FOXC1 expression in CRC cells. Elevated FOXC1 emerged as a critical element, promoting the transcription of serine metabolism enzymes PHGDH, PSAT1, and PSPH, which in turn facilitated serine production, supporting CRC growth. Furthermore, through serine metabolism, FOXC1 influenced purine metabolism and DNA damage repair, thereby increasing 5-FU resistance. Consequently, combining dietary serine restriction with targeted therapy against the ERK1/2-pELK1-FOXC1 axis could be a highly effective strategy for treating CRC, enhancing the efficacy of 5-FU.

Keywords:  5-Fluorouracil resistance; Colorectal cancer; De novo serine synthesis; FOXC1; Metabolic reprogramming

DOI:  https://doi.org/10.1186/s12964-024-02016-8
Anticancer Agents Med Chem. 2025 Jan 01.

CD36 as a Therapeutic Target in Tumor Microenvironment and Lipid Metabolism.

Jiaxuan Li, Jiaqi Chen, Guang Yang, Shulin Zhang, Peiyao Li, Lan Ye.

  Dysregulated lipid metabolism within the tumor microenvironment (TME) is a critical hallmark of cancer progression, with lipids serving as a major energy source for tumor cells. Beyond their role in cell membrane synthesis, lipids also provide essential substrates for biomolecule production and activate signaling pathways that regulate various cellular processes. Aberrant lipid metabolism impacts not only function but also alters the behavior of immune and stromal cells within the TME. CD36, a key lipid transporter, plays a crucial role in regulating fatty acid sensing and lipid metabolism, and its dysregulated expression has been associated with poor prognosis in several cancers. Studies have demonstrated that elevated CD 36 expression in the TME is closely linked to abnormal lipid metabolism, promoting tumor growth, migration, and metastasis. In recent years, significant progress has been made in developing CD36-targeted therapies, including small-molecule inhibitors, antibodies, and nanoparticle-based drugs, with many entering experimental or preclinical stages. This review comprehensively summarizes the latest advances in understanding the role of CD36 in the TME, focusing on its metabolic regulatory mechanisms in tumor cells, immune cells, and stromal cells. Additionally, it highlights the contribution of CD36 to immune evasion, drug resistance, and cancer stem cell maintenance while discussing several therapeutic strategies targeting CD36, including novel therapies currently in clinical trials. By exploring the therapeutic potential of CD36, this review provides critical insights for the future development of CD36-targeted cancer therapies.

Keywords:  CD36; cancer stem cells.; lipid metabolism; targeted therapy; tumor microenvironment

DOI:  https://doi.org/10.2174/0118715206353634241111113338
Biochim Biophys Acta Mol Basis Dis. 2025 Jan 04. pii: S0925-4439(25)00003-1. [Epub ahead of print]1871(3): 167658

YY2-CYP51A1 signaling suppresses hepatocellular carcinoma progression by restraining de novo cholesterol biosynthesis.

Lingxian Wang, Wei Duan, Cao Ruan, Jingyi Liu, Makoto Miyagishi, Vivi Kasim, Shourong Wu.

  Lipid accumulation is a frequently observed characteristic of cancer. Lipid accumulation is closely related to tumor progression, metastasis, and drug resistance; however, the mechanism underlying lipid metabolic reprogramming in tumor cells is not fully understood. Yin yang 2 (YY2) is a C2H2‑zinc finger transcription factor that exerts tumor-suppressive effects. However, its involvement in tumor cell lipid metabolic reprogramming remains unclear. In the present study, we identified YY2 as a novel regulator of cholesterol metabolism. We showed that YY2 suppressed cholesterol accumulation in hepatocellular carcinoma (HCC) cells by downregulating the transcriptional activity of cytochrome P450 family 51 subfamily A member 1 (CYP51A1), a key enzyme in de novo cholesterol biosynthesis. Subsequently, through in vitro and in vivo experiments, we demonstrated that this downregulation is crucial for the YY2 tumor suppressive effect. Together, our findings unraveled a previously unprecedented regulation of HCC cells cholesterol metabolism, and eventually, their tumorigenic potential, through YY2 negative regulation on CYP51A1 expression. This study revealed a novel regulatory mechanism of lipid metabolic reprogramming in tumor cells and provided insights into the molecular mechanism underlying the YY2 the suppressive effect. Furthermore, our findings suggest a potential antitumor therapeutic strategy targeting cholesterol metabolic reprogramming using YY2.

Keywords:  CYP51A1; Lipid metabolic reprogramming; Metabolic reprogramming; YY2; de novo cholesterol biosynthesis

DOI:  https://doi.org/10.1016/j.bbadis.2025.167658
Cancer Res. 2025 Jan 09.

Oxidative Phosphorylation is a Metabolic Vulnerability of Endocrine Therapy-Tolerant Persister Cells in ER+ Breast Cancer.

Steven Tau, Mary D Chamberlin, Huijuan Yang, Jonathan D Marotti, Patricia C Muskus, Alyssa M Roberts, Melissa M Carmichael, Lauren Cressey, Christo Philip C Dragnev, Eugene Demidenko, Riley A Hampsch, Shannon M Soucy, Fred W Kolling, Kimberley S Samkoe, James V Alvarez, Arminja N Kettenbach, Todd W Miller.

Despite adjuvant treatment with endocrine therapies, estrogen receptor-positive (ER+) breast cancers recur in a significant proportion of patients. Recurrences are attributable to clinically undetectable endocrine-tolerant persister cancer cells that retain tumor-forming potential. Therefore, strategies targeting such persister cells may prevent recurrent disease. Using CRISPR-Cas9 genome-wide knockout screening in ER+ breast cancer cells, we identified a survival mechanism involving metabolic reprogramming with reliance upon mitochondrial respiration in endocrine-tolerant persister cells. Quantitative proteomic profiling showed reduced levels of glycolytic proteins in persisters. Metabolic tracing of glucose revealed an energy-depleted state in persisters where oxidative phosphorylation was required to generate ATP. A phase II clinical trial was conducted to evaluate changes in mitochondrial markers in primary ER+/HER2- breast tumors induced by neoadjuvant endocrine therapy (NCT04568616). In an analysis of tumor specimens from 32 patients, tumors exhibiting residual cell proliferation after aromatase inhibitor-induced estrogen deprivation with letrozole showed increased mitochondrial content. Genetic profiling and barcode lineage tracing showed that endocrine-tolerant persistence occurred stochastically without genetic predisposition. Pharmacological inhibition of mitochondrial complex I suppressed the tumor-forming potential of persisters in mice and synergized with the anti-estrogen fulvestrant to induce regression of patient-derived xenografts. These findings indicate that mitochondrial metabolism is essential in endocrine-tolerant persister ER+ breast cancer cells and warrant the development of treatment strategies to leverage this vulnerability for treating breast cancer.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-1204
bioRxiv. 2024 Dec 29. pii: 2024.12.28.630631. [Epub ahead of print]

Metabolic Switch in Endocrine Resistant Estrogen Receptor Positive Breast Cancer.

Heather M Brechbuhl, Amy Han, Kiran Vinod Paul, Travis Nemkov, Srinivas Ramachandran, Ashley Ward, Britta M Jacobsen, Kirk Hansen, Carol A Sartorius, Angelo D'Alessandro, Peter Kabos.

   Purpose: The development of endocrine resistance remains a significant challenge in the clinical management of estrogen receptor-positive (ER+) breast cancer. Metabolic reprogramming is a prominent component of endocrine resistance and a potential therapeutic intervention point. However, a limited understanding of which metabolic changes are conserved across the heterogeneous landscape of ER+ breast cancer or how metabolic changes factor into ER DNA binding patterns hinder our ability to target metabolic adaptation as a treatment strategy. This study uses dimethyl fumarate (DMF) to restore tamoxifen (Tam) and fulvestrant (Fulv) sensitivity in endocrine-resistant cell lines and investigates how metabolic changes influence ER DNA-binding patterns.
Experimental Design: To address the challenge of metabolic adaptation in anti-endocrine resistance, we generated Tam and Fulv resistance in six ER+ breast cancer (BC) cell lines, representing ductal (MCF7, T47D, ZR75-1, and UCD12), lobular (MDA-MB-134--VI), and HER2 amplified (BT474) BC molecular phenotypes. Metabolomic profiling, RNA sequencing, proteomics, and CUT&RUN assays were completed to characterize metabolic shifts, transcriptional and protein changes, and ER DNA-binding patterns in resistant cells. Dimethyl fumarate was assessed for its ability to reverse Tam and Fulv resistance, restore tricarboxylic acid cycle (TCA) cycle function, and restore parental cell (endocrine sensitive) ER DNA binding patterns.
Results: Tamoxifen-resistant (TamR) and fulvestrant-resistant (FulvR) cells exhibited disrupted TCA cycle activity, reduced glutathione levels, and altered nucleotide and amino acid metabolism. DMF treatment replenished TCA cycle intermediates and reversed resistance in both TamR and FulvR cells. DMF also increased mevalonate pathway enzyme expression in both TamR and FulvR cells, with TamR cells upregulating enzymes in the cholesterol synthesis phase and FulvR enhancing enzymes in the early part of the pathway. DMF restored ER DNA-binding patterns in TamR cells to resemble parental cells, re-sensitizing them to Tam. In FulvR cells, DMF reversed resistance by modulating ER-cofactor interactions but did not restore parental ER DNA-binding signatures.
Conclusions: Our findings provide new insights into how metabolic reprogramming affects ER DNA-binding activity in endocrine-resistant breast cancer. We demonstrate how altering metabolism can reprogram ER signaling and influence resistance mechanisms by targeting metabolic vulnerabilities, such as TCA cycle disruptions. Additionally, our data provide a comprehensive metabolomic, RNA-seq, and CUT&RUN data set relevant to tumor metabolic adaptation leading to acquired endocrine resistance in highly utilized ER+ breast cancer cell lines. This study improves our understanding of how metabolic states alter ER function in endocrine-resistant breast cancer.

Keywords:  Breast Cancer; Endocrine Resistance; Estrogen Receptor; Metabolism

DOI:  https://doi.org/10.1101/2024.12.28.630631
Nat Commun. 2025 Jan 08. 16(1): 509

S100P is a ferroptosis suppressor to facilitate hepatocellular carcinoma development by rewiring lipid metabolism.

Min Yang, Weiwei Cui, Xiaoting Lv, Gaozhong Xiong, Caiyu Sun, Haocheng Xuan, Wei Ma, Xiuling Cui, Yeping Cheng, Lihui Han, Bo Chu.

Ferroptosis is a newly identified programmed cell death induced by iron-driven lipid peroxidation and implicated as a potential approach for tumor treatment. However, emerging evidence indicates that hepatocellular carcinoma (HCC) cells are generally resistant to ferroptosis and the underlying molecular mechanism is poorly understood. Here, our study confirms that S100 calcium binding protein P (S100P), which is significantly up-regulated in ferroptosis-resistant HCC cells, efficiently inhibits ferroptosis. Mechanistically, S100P facilitates lysosomal degradation of acetyl-CoA carboxylase alpha (ACC1), which is indispensable for de novo biosynthesis of lipids. Loss of S100P elevates the expression of ACC1 and promotes ferroptotic sensitivity of HCC cells. S100P-mediated ACC1 degradation relies on RAB5C, which directs ACC1 to lysosome via P62-dependent selective autophagy. Knockdown of RAB5C or P62 abrogates S100P-induced lysosomal degradation of ACC1 and restores resistance of HCC cells to ferroptosis. Our work reveals an alternative anti-ferroptosis pathway and suggests S100P as a promising druggable target for ferroptosis-related therapy of HCC.

DOI: https://doi.org/10.1038/s41467-024-55785-8
Redox Biol. 2024 Dec 31. pii: S2213-2317(24)00458-0. [Epub ahead of print]80 103480

De novo lipogenesis protects dormant breast cancer cells from ferroptosis and promotes metastasis.

Beatriz Puente-Cobacho, Cintia Esteo, Patricia Altea-Manzano, Jose Luis Garcia-Perez, José L Quiles, Pedro Sanchez-Rovira, María D Martín-Salvago, Lucía Molina-Jiménez, Rafael J Luque, Sarah-Maria Fendt, Laura Vera-Ramirez.

  Dormant disseminated tumor cells (DTCs) remain viable for years to decades before establishing a clinically overt metastatic lesion. DTCs are known to be highly resilient and able to overcome the multiple biological hurdles imposed along the metastatic cascade. However, the specific metabolic adaptations of dormant DTCs remain to be elucidated. Here, we reveal that dormant DTCs upregulate de novo lipogenesis and favor the activation and incorporation of monounsaturated fatty acids (MUFAs) to their cellular membranes through the activation of acyl-coenzyme A synthetase long-chain family member 3 (ACSL3). Pharmacologic inhibition of de novo lipogenesis or genetic knockdown of ACSL3 results in lipid peroxidation and non-apoptotic cell death through ferroptosis. Clinically, ACSL3 was found to be overexpressed in quiescent DTCs in the lymph nodes of breast cancer patients and to significantly correlate with shorter disease-free and overall survival. Our work provides new insights into the molecular mechanisms enabling the survival of dormant DTCs and supports the use of de novo lipogenesis inhibitors to prevent breast cancer metastasis.

Keywords:  Breast cancer; Ferroptosis; Lipid metabolism; Lipid peroxidation; Metastasis; Monounsaturated fatty acids activation; Tumor cell dormancy

DOI:  https://doi.org/10.1016/j.redox.2024.103480
Sci Rep. 2025 Jan 07. 15(1): 1061

Inosine monophosphate dehydrogenase 2 (IMPDH2) modulates response to therapy and chemo-resistance in triple negative breast cancer.

Tatiane da Silva Fernandes, Bryan M Gillard, Tao Dai, Jeffrey C Martin, Kanita A Chaudhry, Scott M Dugas, Alyssa A Fisher, Pia Sharma, RongRong Wu, Kristopher M Attwood, Subhamoy Dasgupta, Kazuaki Takabe, Spencer R Rosario, Anna Bianchi-Smiraglia.

  Triple negative breast cancer (TNBC) is one of the deadliest subtypes of breast cancer, whose high frequency of relapse is often due to resistance to chemotherapy. Here, we identify inosine monophosphate dehydrogenase 2 (IMPDH2) as a contributor to doxorubicin resistance, in multiple TNBC models. Analysis of publicly available datasets reveals elevated IMPDH2 expression to associate with worse overall TNBC prognosis in the clinic, including lower recurrence-free survival post adjuvant/neoadjuvant therapy. Importantly, both genetic depletion and pharmacological inhibition of IMPDH2 leads to reduction of pro-tumorigenic phenotypes in multiple doxorubicin-resistant TNBC models, both in vitro and in vivo. Overall, we propose IMPDH2 as a novel vulnerability that could be leveraged therapeutically to suppress and/or prevent the growth of chemo-resistant lesions.

Keywords:  Chemo-resistance; Doxorubicin; GTP metabolism; IMPDH2; Paclitaxel; Ribavirin; TNBC

DOI:  https://doi.org/10.1038/s41598-024-85094-5
Ann Hematol. 2025 Jan 04.

Metabolic reprogramming induced by PSMA4 overexpression facilitates bortezomib resistance in multiple myeloma.

Han Yu, Chengli Wu, Jie He, Yajun Zhang, Qiqi Cao, Hongyan Lan, Hongshan Li, Chengyang Xu, Chen Chen, Rong Li, Bo Zheng.

  Multiple myeloma(MM) remains incurable with high relapse and chemoresistance rates. Differentially expressed genes(DEGs) between newly diagnosed myeloma and secondary plasma cell leukemia(sPCL) were subjected to a weighted gene co-expression network analysis(WGCNA). Drug resistant myeloma cell lines were established. Seahorse XF analyzer was applied to detect the metabolism reprogramming associated with the hub gene. The metabolic relevance and the underlying mechanism of the hub gene in myeloma resistance were explored via in vitro experiments. A total of 1310 DEGs were used to construct five co-expression modules. Gene function enrichment analysis demonstrated that candidate hub genes were closely related to oxidative phosphorylation. We performed prognostic analysis and identified PSMA4 as the key hub gene related to the extramedullary invasion of myeloma. The in vitro experiments demonstrated bortezomib resistant myeloma cell lines exhibited high PSMA4 expression, improved oxidative phosphorylation activity with increased ROS level. PSMA4 knockdown re-sensitize resistant myeloma cells via suppressing oxidative phosphorylation activity. Further investigation revealed that PSMA4 induced a hypoxia state which activated the HIF-1α signaling pathway. PSMA4 induces metabolic reprogramming by improving oxidative phosphorylation activity which accounts for the hypoxia state in myeloma cell. The activated HIF-1α signaling pathway causes bortezomib resistance via promoting anti-apoptotic activity in myeloma.

Keywords:  Bortezomib resistance; Metabolic reprogramming; Myeloma; WGCNA

DOI:  https://doi.org/10.1007/s00277-024-06163-3
PLoS One. 2025 ;20(1): e0312424

The role of mitochondrial dysfunction in the cytotoxic synergistic effect of gemcitabine and arsenic on breast cancer.

Farshid Maleki, Somayeh Handali, Mohsen Rezaei.

Breast cancer is the most common type of cancer in women worldwide. A common approach to cancer treatment in clinical practice is to use a combination of drugs to enhance the anticancer activity of drugs while reducing their side effects. In this regard, we evaluated the effectiveness of combined treatment with gemcitabine (GCB) and arsenic (ATO) and how they affect the cell death pathway in cancer cells. Cytotoxic activity of drugs individually or combined against MDA-MB-231 and MCF-7 was performed by MTT method and isobolographic analysis was used to determine the interaction between these factors. The combination of ATO and GCB showed synergistic anti-cancer activity (CI < 1) in both cancer cell lines. The combination of ATO and GCB induced sub-G1 phase arrest, apoptosis and death rates in MCF-7 and MDA-MB-231 cells. The apoptotic response induced by the combination of GCB and ATO was dependent on caspase 3/7. Combined treatment with mitochondrial membrane potential (MMP) reduction and increased reactive oxygen species (ROS) production caused mitochondrial dysfunction. Co-treatment significantly reduced catalase (CAT) activity in both cancer cells compared to the control group and cells treated with each monotherapy. A significant decrease in cellular GSH was observed in cancer cells treated with ATO and GCB. In addition, migration and invasion were significantly reduced in breast cancer cells treated with the combination of ATO and GCB compared to cells treated with ATO and GCB. In conclusion, the combined treatment of ATO and GCB synergistically increased the anti-cancer activity, and these findings provide an effective approach for the treatment of breast cancer. To the best of our knowledge, this is the first study showing promising results for combination therapy with ATO and GCB in breast cancer.

DOI: https://doi.org/10.1371/journal.pone.0312424
Int J Radiat Biol. 2025 Jan 10. 1-12

FASN inhibition shows the potential for enhancing radiotherapy outcomes by targeting glycolysis, AKT, and ERK pathways in breast cancer.

Ching-I Chen, Deng-Yu Kuo, Hui-Yen Chuang.

   PURPOSE: Breast cancer ranks as the most prevalent cancer in women, characterized by heightened fatty acid synthesis and glycolytic activity. Fatty acid synthase (FASN) is prominently expressed in breast cancer cells, regulating fatty acid synthesis, thereby enhancing tumor growth and migration, and leading to radioresistance. This study aims to investigate how FASN inhibition affects cell proliferation, migration, and radioresistance in breast cancer, as well as the mechanisms involved.
MATERIALS AND METHODS: We used lentiviruses carrying shFASN to create FASN-knockdown cell lines called MCF-7-shFASN and MDA-MB-231-shFASN. We conducted Western blot analysis to determine the expression levels of FASN and other proteins of interest. Furthermore, we evaluated cellular glucose uptake and migration using the 18F-FDG assay, wound healing, and transwell assays. We also employed the MTT assay to assess the short-term survival of the negative control and FASN-knockdown cells after irradiation.
RESULTS: FASN knockdown led to a decrease in the expressions of proteins related to fatty acid synthesis and glycolysis in both MCF-7-shFASN and MDA-MB-231-shFASN cells when compared to their counterparts. Moreover, reduced 18F-FDG uptake and lactate production were also detected after FASN knockdown. FASN knockdown inhibited cell proliferation and survival by downregulating the AKT, ERK, and AMPK pathways and promoted apoptosis by increasing the BAX/p-Bcl-2 ratio. In addition, FASN knockdown impaired cell migration while enhancing radiosensitivity.
CONCLUSIONS: FASN knockdown disrupts fatty acid synthesis and glycolysis, inhibits cell proliferation and induces apoptosis. The increased radiosensitivity after FASN inhibition suggests that it could potentially complement radiotherapy in treating breast cancer.

Keywords:  Fatty acid synthase; breast cancer; glucose; metabolism; radiosensitivity

DOI:  https://doi.org/10.1080/09553002.2024.2446585
Front Oncol. 2024 ;14 1499125

Targeting ferroptosis: a promising strategy to overcome drug resistance in breast cancer.

Cuixin Peng, Yanning Chen, Mingzhang Jiang.

  Breast cancer is one of the most prevalent malignancies affecting women worldwide, with its incidence increasingly observed in younger populations. In recent years, drug resistance has emerged as a significant challenge in the treatment of breast cancer, making it a central focus of contemporary research aimed at identifying strategies to overcome this issue. Growing evidence indicates that inducing ferroptosis through various mechanisms, particularly by inhibiting System Xc-, depleting glutathione (GSH), and inactivating glutathione peroxidase 4 (GPX4), holds great potential in overcoming drug resistance in breast cancer. It is anticipated that therapies targeting ferroptosis will emerge as a promising strategy to reverse tumor resistance, offering new hope for breast cancer patients. This review will explore the latest advancements in understanding ferroptosis in the context of breast cancer drug resistance, with a particular emphasis on the roles of ferroptosis inducers and inhibitors, and the impact of ferroptotic pathways on overcoming drug resistance in breast cancer.

Keywords:  antitumor mechanism; breast cancer; chemotherapy resistance; ferroptosis; iron metabolism

DOI:  https://doi.org/10.3389/fonc.2024.1499125
iScience. 2024 Dec 20. 27(12): 111488

Amitriptyline revitalizes ICB response via dually inhibiting Kyn/Indole and 5-HT pathways of tryptophan metabolism in ovarian cancer.

Junyang Li, Bingjie Mei, Lu Feng, Xiaoxin Wang, Dengfeng Wang, Jianming Huang, Guonan Zhang.

  Reprogramming tryptophan metabolism (TRP) may be able to overcome immunosuppression and restore the immune checkpoint blockade (ICB) response in patients with epithelial ovarian cancer (EOC) resistant to ICB therapy because TRP metabolism is involved in the kynurenine/indole and serotonin pathways of tryptophan metabolism. Herein, employing amitriptyline (AMI), an antagonist of TLR4 and serotonin transporter (SERT), we revealed that AMI remodels the immunological landscape of EOC. In particular, AMI lowered the expression of IDO1, IL-4I1, and PD-L1, the quantity of KYN and indoles, and the level of immunosuppressive immune cells MDSC, Tregs, and CD8+CD39+/PD-1+ T cell. AMI boosted the killing potential of anti-PD-1-directed CD8+T cells and worked in concert with PD-1 inhibitors to suppress tumor growth and to prolong the survival of EOC-bearing mice. This work highlights AMI as an effective regulator of ICB response by manipulating EOC cell TRP metabolism, indicating it could be a potential strategy for improving EOC ICB therapy.

Keywords:  Cancer; Immune response; Microenvironment

DOI:  https://doi.org/10.1016/j.isci.2024.111488
J Exp Clin Cancer Res. 2025 Jan 09. 44(1): 10

ONC213: a novel strategy to resensitize resistant AML cells to venetoclax through induction of mitochondrial stress.

Jenna L Carter, Yongwei Su, Eman T Al-Antary, Jianlei Zhao, Xinan Qiao, Guan Wang, Holly Edwards, Lisa Polin, Juiwanna Kushner, Sijana H Dzinic, Kathryn White, Steven A Buck, Maik Hüttemann, Joshua E Allen, Varun V Prabhu, Jay Yang, Jeffrey W Taub, Yubin Ge.

   BACKGROUND: Venetoclax + azacitidine is a frontline treatment for older adult acute myeloid leukemia (AML) patients and a salvage therapy for relapsed/refractory patients who have been treated with intensive chemotherapy. While this is an important treatment option, many patients fail to achieve complete remission and of those that do, majority relapse. Leukemia stem cells (LSCs) are believed to be responsible for AML relapse and can be targeted through oxidative phosphorylation reduction. We previously reported that ONC213 disrupts oxidative phosphorylation and decreases Mcl-1 protein, which play a key role in venetoclax resistance. Here we investigated the antileukemic activity and underlying molecular mechanism of the combination of ONC213 + venetoclax against AML cells.
METHODS: Flow cytometry was used to determine drug-induced apoptosis. Protein level changes were determined by western blot. An AML cell line-derived xenograft mouse model was used to determine the effects of ONC213 + venetoclax on survival. A patient-derived xenograft (PDX) mouse model was used to determine drug effects on CD45+/CD34+/CD38-/CD123 + cells. Colony formation assays were used to assess drug effects on AML progenitor cells. Mcl-1 and Bax/Bak knockdown and Mcl-1 overexpression were used to confirm their role in the mechanism of action. The effect of ONC213 + venetoclax on mitochondrial respiration was determined using a Seahorse bioanalyzer.
RESULTS: ONC213 + venetoclax synergistically kills AML cells, including those resistant to venetoclax alone as well as venetoclax + azacitidine. The combination significantly reduced colony formation capacity of primary AML progenitors compared to the control and either treatment alone. Further, the combination prolonged survival in an AML cell line-derived xenograft model and significantly decreased LSCs in an AML PDX model.
CONCLUSIONS: ONC213 can resensitize VEN + AZA-resistant AML cells to venetoclax therapy and target LSCs ex vivo and in vivo.

Keywords:  Acute myeloid leukemia; Azacitidine; ONC213; Venetoclax

DOI:  https://doi.org/10.1186/s13046-024-03267-6
FASEB J. 2025 Jan 15. 39(1): e70308

The histone lactylation of AIM2 influences the suppression of ferroptosis by ACSL4 through STAT5B and promotes the progression of lung cancer.

Songze Wu, Man Liu, Xu Wang, Shan Wang.

  Lung cancer progression is characterized by intricate epigenetic changes that impact critical metabolic processes and cell death pathways. In this study, we investigate the role of histone lactylation at the AIM2 locus and its downstream effects on ferroptosis regulation and lung cancer progression. We utilized a combination of biochemical assays, including chromatin immunoprecipitation (ChIP), quantitative real-time PCR (qRT-PCR), and western blotting to assess histone lactylation levels and gene expression. To evaluate the functional consequences, we employed gain- and loss-of-function approaches using shikonin treatment and siRNA knockdowns in lung cancer cell lines. Additionally, we assessed the impact of these interventions on ferroptosis markers and lung cancer cell viability. Our results reveal that increased histone lactylation at the AIM2 locus correlates with enhanced transcriptional activity of AIM2, leading to reduced ferroptosis through modulation of ACSL4 and STAT5B. Furthermore, we demonstrate that shikonin, a natural naphthoquinone derivative, effectively downregulates PKM2 and AIM2 expression, thereby inhibiting lung cancer progression by counteracting the effects of histone lactylation on AIM2 expression. These findings highlight the importance of histone lactylation in regulating AIM2 expression and ferroptosis in lung cancer cells. They also suggest that targeting PKM2 and AIM2, particularly through the use of shikonin, could be a promising strategy for developing novel therapies against lung cancer.

Keywords:  AIM2; PD‐1; ferroptosis; histone lactylation; lung cancer

DOI:  https://doi.org/10.1096/fj.202402139R
Cells. 2024 Dec 27. pii: 18. [Epub ahead of print]14(1):

Strategies to Overcome Intrinsic and Acquired Resistance to Chemoradiotherapy in Head and Neck Cancer.

Tycho de Bakker, Anouk Maes, Tatiana Dragan, Philippe Martinive, Sébastien Penninckx, Dirk Van Gestel.

  Definitive chemoradiotherapy (CRT) is a cornerstone of treatment for locoregionally advanced head and neck cancer (HNC). Research is ongoing on how to improve the tumor response to treatment and limit normal tissue toxicity. A major limitation in that regard is the growing occurrence of intrinsic or acquired treatment resistance in advanced cases. In this review, we will discuss how overexpression of efflux pumps, perturbation of apoptosis-related factors, increased expression of antioxidants, glucose metabolism, metallotheionein expression, increased DNA repair, cancer stem cells, epithelial-mesenchymal transition, non-coding RNA and the tumour microenvironment contribute towards resistance of HNC to chemotherapy and/or radiotherapy. These mechanisms have been investigated for years and been exploited for therapeutic gain in resistant patients, paving the way to the development of new promising drugs. Since in vitro studies on resistance requires a suitable model, we will also summarize published techniques and treatment schedules that have been shown to generate acquired resistance to chemo- and/or radiotherapy that most closely mimics the clinical scenario.

Keywords:  acquired resistance; chemoradiotherapy; chemoresistance; head and neck; intrinsic resistance; radioresistance

DOI:  https://doi.org/10.3390/cells14010018
bioRxiv. 2024 Dec 20. pii: 2024.12.18.628944. [Epub ahead of print]

Statins inhibit onco-dimerization of the 4Ig isoform of B7-H3.

Margie N Sutton, Sarah E Glazer, Ajlan Al Zaki, Arianna Napoli, Ping Yang, Priya Bhosale, Jinsong Liu, Seth T Gammon, David Piwnica-Worms.

B7-H3 (CD276), a member of the B7-family of immune checkpoint proteins, has been shown to have immunological and non-immunological effects promoting tumorigenesis [1, 2] and expression correlates with poor prognosis for many solid tumors, including cervical, ovarian and breast cancers [3-6]. We recently identified a tumor-cell autochthonous tumorigenic role for dimerization of the 4Ig isoform of B7-H3 (4Ig-B7-H3) [7], where 4Ig-B7-H3 dimerization in cis activated tumor-intrinsic cellular proliferation and tumorigenesis pathways, providing a novel opportunity for therapeutic intervention. Herein, a live cell split-luciferase complementation strategy was used to visualize 4Ig-B7-H3 homodimerization in a high-throughput small molecule screen (HTS) to identify modulators of this protein-protein interaction (PPI). Notably, the HTS identified several compounds that converged on lipid metabolism (including HMG-CoA reductase inhibitors, also known as statins) as significant inhibitors of 4Ig-B7-H3 dimerization (p < 0.01). In vitro and in vivo murine studies provided evidence that statin-mediated disruption of 4Ig-B7-H3 dimerization was associated with anti-tumor effects. Statin-mediated anti-cancer efficacy was selective for B7-H3-expressing tumors and retrospective analysis of clinical tumor specimens supported the hypothesis that concurrent statin use enhanced clinical outcomes for patients in a B7-H3 restricted manner. Thus, disruption of 4Ig-B7-H3 dimerization provides an unanticipated molecular mechanism linking statin use in cancer therapy and prevention with immune checkpoint.

DOI: https://doi.org/10.1101/2024.12.18.628944
FASEB J. 2025 Jan 15. 39(1): e70294

Seryl-tRNA synthetase inhibits Wnt signaling and breast cancer progression and metastasis.

Lei Jiang, Justin Wang, Ze Liu, Qian Zhang, Xiang-Lei Yang.

Tumors require ample protein synthesis to grow, and aminoacyl-tRNA synthetases, as critical translation factors, are expected to support cancer progression. Unexpectedly, overexpression of seryl-tRNA synthetase (SerRS) suppresses primary tumor growth of breast cancer. However, the effects of SerRS on metastasis have not been studied. We observe a decrease in SerRS expression in breast cancer patient metastases compared with matched primary tumors, suggesting an inhibitory role of SerRS in metastasis. Through mouse metastasis models using breast cancer cell lines overexpressing SerRS, we show that SerRS impedes not only primary tumor growth but also establishment of metastases, and the effect of SerRS on metastasis can be independent of its impact on the primary tumor. SerRS also inhibits tumor growth with induced, post-tumor-onset overexpression, demonstrating its potential as an anticancer therapeutic. Tumor RNA-seq analysis identified Wnt signaling among the top SerRS-regulated pathways. Using cell-based studies, we confirm SerRS suppresses Wnt signaling and metastatic processes in breast cancer cells. To the best of our knowledge, this is the first study to show a component of the translation machinery can act as both a tumor and metastasis suppressor.

DOI: https://doi.org/10.1096/fj.202401720R
Cell Signal. 2025 Jan 03. pii: S0898-6568(24)00559-X. [Epub ahead of print]127 111583

HDAC inhibitor enhances ferroptosis susceptibility of AML cells by stimulating iron metabolism.

Ruipeng Bian, Yingying Shang, Nahua Xu, Baiping Liu, Yanni Ma, Hui Li, Jieping Chen, Qi Yao.

  Acute Myeloid Leukemia (AML) are challenging blood cancers with limited long-term survival rates, necessitating novel therapeutic strategies. This study explored the role of Histone deacetylase (HDAC) inhibitors in enhancing ferroptosis in AML cells by modulating iron metabolism. We demonstrated that HDAC inhibitors (Entinostat and Vorinostat) sensitize AML cells to ferroptosis both in vitro and in vivo. Mechanistically, we show that HDAC inhibitor treatment upregulated the expression of iron metabolism genes that lead to increased labile iron pool. Notably, NCOA4, a ferritin degradation mediator, and HMOX1/2 proteins, involved in heme breakdown, were identified as critical contributors to this process. The functional role of these genes was confirmed through CRISPR-Cas9 mediated knockouts, which significantly rescued cells from HDAC-induced ferroptosis sensitivity. Our results suggest a novel therapeutic approach for AML, where combining HDAC inhibitors with ferroptosis inducers could exploit the disrupted iron metabolism in AML cells. This study highlights the potential of HDAC inhibitors to modulate iron metabolism pathways, offering new insights into the treatment of these malignancies.

Keywords:  AML; Ferroptosis; HDAC inhibitors; Iron metabolism

DOI:  https://doi.org/10.1016/j.cellsig.2024.111583
J Colloid Interface Sci. 2024 Dec 31. pii: S0021-9797(24)03081-9. [Epub ahead of print]683(Pt 2): 890-905

Dual-template epitope imprinted nanoparticles for anti-glycolytic tumor-targeted treatment.

Da-Wei Wang, Xing-Hui Ren, Yao-Jia Ma, Fang-Qi Wang, Xi-Wen He, Wen-You Li, Yu-Kui Zhang.

  Glycolysis provides tumors with abundant nutrients through glucose (Glu) metabolism. As a therapeutic target, precise targeting and effective inhibition of the glycolysis process remains a major challenge in anti-metabolic therapy. In this study, a novel dual-template molecularly imprinted polymer (D-MIP), capable of specifically recognizing glucose transporter member 1 (GLUT1) and hexokinase-2 (HK2) was prepared for anti-glycolytic tumor therapy. The imprinting factors of D-MIP for the recognition of the template molecules, the GLUT1 epitope and the HK2 epitope, were 2.1 and 2.5, respectively, enabling specific recognition of the entire target protein. Targeting GLUT1 with D-MIP could impede its Glu uptake, while simultaneously inhibiting the activity of cytoplasmic HK2, thereby reducing the metabolic rate of Glu. Cell experiments demonstrated that inhibition of HK2 resulted in downregulation of the downstream, products glucose-6-phosphate (6PG) and lactate (LA). In vitro and in vivo experimental results indicated that D-MIP exhibited significant targeting and inhibitory effects on GLUT1 and HK2, respectively, which suppressed tumor glycolysis and induced apoptosis in MCF-7 cells. Furthermore, mouse tumor models and hematoxylin-eosin (H&E) staining confirmed the excellent anti-tumor efficacy and favorable biocompatibility of D-MIP. This work represents the first design and development of a dual-template imprinted polymer targeting key transport channels and metabolic enzymes involved in glycolysis, advancing the research and application of anti-glycolytic tumor therapy.

Keywords:  GLUT1; Glycolysis; HK2; Molecular imprinting; Targeting treatment

DOI:  https://doi.org/10.1016/j.jcis.2024.12.227
Front Immunol. 2024 ;15 1512469

Mitochondria: a crucial factor in the progression and drug resistance of colorectal cancer.

Ying Zhao, Xiaomin Guo, Li Zhang, Dongwei Wang, Yan Li.

  Colorectal cancer (CRC), as one of the malignant tumors with the highest incidence and mortality rates worldwide in recent years, originating primarily from the mucosal tissues of the colon or rectum, and has the potential to rapidly develop into invasive cancer. Its pathogenesis is complex, involving a multitude of factors including genetic background, lifestyle, and dietary habits. Early detection and treatment are key to improving survival rates for patients with CRC. However, the pervasive problem is that patients can become severely resistant to treatment, which greatly increases the complexity and challenge of treatment. Therefore, unraveling and overcoming the resistance of CRC has become a focus of research. Mitochondria, the energy centers of the cell, play a crucial role in cellular metabolism, energy supply, and the apoptosis process. In CRC, Mitochondrial dysfunction not only impairs normal cell function but also promotes tumor resistance. Therefore, a deep understanding of the relationship between mitochondrial dysfunction and the mechanisms of CRC development, as well as the mechanisms by which it promotes resistance to chemotherapy drugs, is crucial for the development of targeted therapies, enhancing drug efficacy, and improving treatment outcomes and quality of life for patients.

Keywords:  chemotherapy resistance; colorectal cancer; mitochondria; multimodal analysis techniques; treatment strategies

DOI:  https://doi.org/10.3389/fimmu.2024.1512469
Clin Cancer Res. 2025 Jan 09.

NXP800 activates the unfolded protein response, altering AR and E2F function to impact castration-resistant prostate cancer growth.

Jonathan Welti, Denisa Bogdan, Ines Figueiredo, Ilsa Coleman, Juan Jiménez Vacas, Kate Liodaki, Franziska Weigl, Lorenzo Buroni, Wanting Zeng, Ilona Bernett, Claudia Bertan, Theodoros I Roumeliotis, Amandeep Bhamra, Jan Rekowski, Bora Gurel, Antje J Neeb, Jian Ning, Dapei Li, Veronica S Gil, Ruth Riisnaes, Susana Miranda, Mateus Crespo, Ana Ferreira, Nina Tunariu, Elisa Pasqua, Nicola Chessum, Matthew Cheeseman, Robert Te Poele, Marissa Powers, Suzanne Carreira, Jyoti Choudhary, Paul Clarke, Udai Banerji, Amanda Swain, Keith Jones, Wei Yuan, Paul Workman, Peter S Nelson, Johann S de Bono, Adam Sharp.

PURPOSE: Advanced prostate cancer (PCa) is invariably fatal with the androgen receptor (AR) being a major therapeutic target. AR signaling inhibitors have improved overall survival for men with advanced PCa, but treatment resistance is inevitable and includes reactivation of AR signaling. Novel therapeutic approaches targeting these mechanisms to block tumor growth is an urgent unmet clinical need. One attractive strategy is to target heat shock proteins critical to AR functional activity.
EXPERIMENTAL DESIGN: We first did transcriptome analysis on multiple castration-resistant PCa (CRPC) cohorts to correlate the association between the GO Cellular Response to Heat gene expression signature and overall survival. Next, we analyzed the impact of targeting the heat shock factor 1 (HSF1) pathway, with an inhibitor in clinical development, namely NXP800, in models of treatment-resistant PCa. Finally, we confirmed our mechanistic and phenotypic findings using an NXP800-resistant model and an in-vivo model of CRPC.
RESULTS: We report that in multiple CRPC transcriptome cohorts the GO Cellular Response to Heat gene expression signature associates with AR signaling and worse clinical outcome. We demonstrate the effects of targeting the HSF1 pathway, central to cellular stress, with an inhibitor in clinical development, namely NXP800 (formerly CCT361814), in PCa. Targeting the HSF1 pathway with the inhibitor NXP800 decreases HSP72 expression, activates the unfolded protein response, and inhibits AR- and E2F-mediated activity, inhibiting the growth of treatment-resistant PCa models.
CONCLUSIONS: Overall, NXP800 has anti-tumor activity against treatment-resistant PCa models, including molecular subtypes with limited treatment options, supporting its consideration for PCa-specific clinical development.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-2386
Biomolecules. 2024 Dec 13. pii: 1594. [Epub ahead of print]14(12):

Pharmacological Inhibition of Astrocytic Transglutaminase 2 Facilitates the Expression of a Neurosupportive Astrocyte Reactive Phenotype in Association with Increased Histone Acetylation.

Thomas Delgado, Jacen Emerson, Matthew Hong, Jeffrey W Keillor, Gail V W Johnson.

  Astrocytes play critical roles in supporting structural and metabolic homeostasis in the central nervous system (CNS). CNS injury leads to the development of a range of reactive phenotypes in astrocytes whose molecular determinants are poorly understood. Finding ways to modulate astrocytic injury responses and leverage a pro-recovery phenotype holds promise in treating CNS injury. Recently, it has been demonstrated that ablation of astrocytic transglutaminase 2 (TG2) shifts reactive astrocytes towards a phenotype that improves neuronal injury outcomes both in vitro and in vivo. Additionally, in an in vivo mouse model, pharmacological inhibition of TG2 with the irreversible inhibitor VA4 phenocopied the neurosupportive effects of TG2 deletion in astrocytes. In this study, we extended our comparisons of VA4 treatment and TG2 deletion to provide insights into the mechanisms by which TG2 attenuates neurosupportive astrocytic function after injury. Using a neuron-astrocyte co-culture model, we found that VA4 treatment improves the ability of astrocytes to support neurite outgrowth on an injury-relevant matrix, as we previously showed for astrocytic TG2 deletion. We hypothesize that TG2 mediates its influence on astrocytic phenotype through transcriptional regulation, and our previous RNA sequencing suggests that TG2 is primarily transcriptionally repressive in astrocytes, although it can facilitate both up- and downregulation of gene expression. Therefore, we asked whether VA4 inhibition could alter TG2's interaction with Zbtb7a, a transcription factor that we previously identified as a functionally relevant TG2 nuclear interactor. We found that VA4 significantly decreased the interaction of TG2 and Zbtb7a. Additionally, we assessed the effect of TG2 deletion and VA4 treatment on transcriptionally permissive histone acetylation and found significantly greater acetylation in both experimental groups. Consistent with these findings, our present proteomic analysis further supports the predominant transcriptionally repressive role of TG2 in astrocytes. Our proteomic data additionally unveiled pronounced changes in lipid and antioxidant metabolism in astrocytes with TG2 deletion or inhibition, which likely contribute to the enhanced neurosupportive function of these astrocytes.

Keywords:  astrocytes; lipid metabolism; neurite outgrowth; proteomics; transcriptional regulation

DOI:  https://doi.org/10.3390/biom14121594
Blood. 2024 Dec 27. pii: blood.2024025245. [Epub ahead of print]

α-Ketoglutarate dehydrogenase is a therapeutic vulnerability in acute myeloid leukemia.

Scott Evan Millman, Almudena Chaves-Perez, Sudha Janaki-Raman, Yu-Jui Ho, John P Morris Iv, Varun Narendra, Chi-Chao Chen, Benjamin T Jackson, Jossie J Yashinskie, Riccardo Mezzadra, Tessa I Devine, Valentin J A Barthet, Michelle Saoi, Timour Baslan, Sha Tian, Zohar Sachs, Lydia Ws Finley, Justin R Cross, Scott W Lowe.

Perturbations in intermediary metabolism contribute to the pathogenesis of acute myeloid leukemia (AML) and can produce therapeutically actionable dependencies. Here, we probed whether alpha-ketoglutarate (aKG) metabolism represents a specific vulnerability in AML. Using functional genomics, metabolomics, and mouse models, we identified the aKG dehydrogenase complex, which catalyzes the conversion of aKG to succinyl CoA, as a molecular dependency across multiple models of adverse-risk AML. Inhibition of 2-oxoglutarate dehydrogenase (OGDH), the E1 subunit of the aKG dehydrogenase complex, impaired AML progression and drove differentiation. Mechanistically, hindrance of aKG flux through the tricarboxylic acid (TCA) cycle resulted in rapid exhaustion of aspartate pools and blockade of de novo nucleotide biosynthesis, while cellular bioenergetics was largely preserved. Additionally, increased aKG levels following OGDH inhibition impacted the biosynthesis of other critical amino acids. Thus, this work has identified a previously undescribed, functional link between certain TCA cycle components and nucleotide biosynthesis enzymes across AML. This metabolic node may serve as a cancer-specific vulnerability amenable to therapeutic targeting in AML and perhaps in other cancers with similar metabolic wiring.

DOI: https://doi.org/10.1182/blood.2024025245
Tissue Cell. 2024 Dec 31. pii: S0040-8166(24)00414-2. [Epub ahead of print]93 102713

Targeting Siglec-15 mediates mitochondrial retrograde regulation of cervical cancer development.

Jing Wang, Zenghui Li, Yifan He, Yongli Chu.

  Cervical cancer (CCA) is the predominant cause of fatalities from gynecologic malignancies, with metastasis responsible for 80 % of cancer-related mortalities. This study preliminarily examined the involvement of Sialic Acid Binding Ig Like Lectin 15 (Siglec-15) in the development of CCA and its probable mechanisms. We assessed the capacity of Siglec-15 to modulate CCA progression by establishing knockdown and overexpression Siglec-15 cell lines, supplemented with animal models, using both in vivo and in vitro dual investigations. Our findings indicate that Siglec-15 is significantly expressed in CCA cell lines and is intimately associated with the proliferation, migration, and invasion capabilities of CCA cells, as well as mitochondrial ROS homeostasis. The suppression of Siglec-15 expression markedly reduced tumor growth in mice, potentially due to Siglec-15's role in regulating the Mitogen-Activated Protein Kinase (MAPK) signaling pathway, which mediates the retrograde regulation of mitochondrial ROS homeostasis. Siglec-15 may emerge as a novel therapeutic target and prognostic marker for patients with CCA.

Keywords:  Cervical cancer; MAPK; Mitochondrial retrograde; ROS; Siglec-15

DOI:  https://doi.org/10.1016/j.tice.2024.102713