bims-cadres 2022-08-14 papers

bims-cadres

Biomed News

on Cancer drug resistance

Issue of 2022–08–14
eightteen papers selected by
Rana Gbyli, Yale University

Inhibition of the Phospholipase Cε-c-Jun N-Terminal Kinase Axis Suppresses Glioma Stem Cell Properties.
Sodium selenite inhibits proliferation and metastasis through ROS-mediated NF-κB signaling in renal cell carcinoma.
shRNA‑mediated knockdown of KNTC1 inhibits non-small-cell lung cancer through regulating PSMB8.
The MARCHF6 E3 ubiquitin ligase acts as an NADPH sensor for the regulation of ferroptosis.
Induction of apoptosis through inactivation of ROS-dependent PI3K/Akt signaling pathway by platycodin D in human bladder urothelial carcinoma cells.
CircKPNB1 mediates a positive feedback loop and promotes the malignant phenotypes of GSCs via TNF-α/NF-κB signaling.
A complex epigenome-splicing crosstalk governs epithelial-to-mesenchymal transition in metastasis and brain development.
Dysregulation of SIRT3 SUMOylation Confers AML Chemoresistance via Controlling HES1-Dependent Fatty Acid Oxidation.
Genetic alterations of Keap1 confers chemotherapeutic resistance through functional activation of Nrf2 and Notch pathway in head and neck squamous cell carcinoma.
IKKε Inhibitor Amlexanox Promotes Olaparib Sensitivity through the C/EBP-β-Mediated Transcription of Rad51 in Castrate-Resistant Prostate Cancer.
p38 MAPK-dependent phosphorylation of transcription factor SOX2 promotes an adaptive response to BRAF inhibitors in melanoma cells.
Histone lysine demethylase inhibition reprograms prostate cancer metabolism and mechanics.
BARX2/FOXA1/HK2 axis promotes lung adenocarcinoma progression and energy metabolism reprogramming.
Isothiocyanates (ITCs) 1-(Isothiocyanatomethyl)-4-phenylbenzene and 1-Isothiocyanato-3,5-bis(trifluoromethyl)benzene-Aldehyde Dehydrogenase (ALDH) Inhibitors, Decreases Cisplatin Tolerance and Migratory Ability of NSCLC.
Polyploidy as an Adaptation against Loss of Heterozygosity in Cancer.
Combination of PAKs inhibitors IPA-3 and PF-3758309 effectively suppresses colon carcinoma cell growth by perturbing DNA damage response.
Co-targeting of specific epigenetic regulators in combination with CDC7 potently inhibit melanoma growth.
Oxidative stress-mediated mitochondrial fission promotes hepatic stellate cell activation via stimulating oxidative phosphorylation.

Int J Mol Sci. 2022 Aug 07. pii: 8785. [Epub ahead of print]23(15):

Inhibition of the Phospholipase Cε-c-Jun N-Terminal Kinase Axis Suppresses Glioma Stem Cell Properties.

Masashi Okada, Yurika Nakagawa-Saito, Yuta Mitobe, Asuka Sugai, Keita Togashi, Shuhei Suzuki, Chifumi Kitanaka.

  Glioma stem cells (GSCs), the cancer stem cells of glioblastoma multiforme (GBM), contribute to the malignancy of GBM due to their resistance to therapy and tumorigenic potential; therefore, the development of GSC-targeted therapies is urgently needed to improve the poor prognosis of GBM patients. The molecular mechanisms maintaining GSCs need to be elucidated in more detail for the development of GSC-targeted therapy. In comparison with patient-derived GSCs and their differentiated counterparts, we herein demonstrated for the first time that phospholipase C (PLC)ε was highly expressed in GSCs, in contrast to other PLC isoforms. A broad-spectrum PLC inhibitor suppressed the viability of GSCs, but not their stemness. Nevertheless, the knockdown of PLCε suppressed the survival of GSCs and induced cell death. The stem cell capacity of residual viable cells was also suppressed. Moreover, the survival of mice that were transplanted with PLCε knockdown-GSCs was longer than the control group. PLCε maintained the stemness of GSCs via the activation of JNK. The present study demonstrated for the first time that PLCε plays a critical role in maintaining the survival, stemness, and tumor initiation capacity of GSCs. Our study suggested that PLCε is a promising anti-GSC therapeutic target.

Keywords:  brain tumor initiating cell; c-Jun N-terminal kinase; glioma initiating cell; phospholipase Cε

DOI:  https://doi.org/10.3390/ijms23158785
BMC Cancer. 2022 Aug 09. 22(1): 870

Sodium selenite inhibits proliferation and metastasis through ROS-mediated NF-κB signaling in renal cell carcinoma.

Xiao Liu, Meng Jiang, Chenggang Pang, Jianning Wang, Lijuan Hu.

   BACKGROUND: Sodium selenite (SSE) has been reported to exert anti-tumor effects in several cancer cells. However, the underlying mechanisms in renal cancer are yet to be elucidated. The effects of SSE on the proliferation, metastasis, and apoptosis of renal cancer cells, as well as its mechanism, were investigated in this study.
METHODS: ACHN and 786-O renal cancer cells were treated with different concentrations of SSE, MTT, and colony formation assays were used to detect the proliferation ability of cells. The migration of cells was detected using scratch-wound-healing and transwell-migration assays. The effect of SSE on apoptosis was assessed by AnnexinV-FITC/PI double staining. Besides, Western blotting was employed to detect the protein-expression level and elucidate the underlying pathways. We also made subcutaneous xenografts in athymic mice to verify the effect of SSE on tumor growth in vivo.
RESULTS: Our results demonstrated that treatment with SSE resulted in significant inhibition of cell proliferation and migration. Flow cytometry and Western blot confirmed that SSE induced apoptosis via the endogenous apoptotic pathway. We also confirmed that SSE treatment causes an increase in intracellular reactive oxygen species (ROS) levels, resulting in the inhibition of nuclear transcription factor-κB (NF-κB) signaling. Modulation of the ROS level by the chemical inhibitor N-acetyl-cysteine reversed the effect of SSE on cells. Similarly, subcutaneous xenografts in athymic mice models showed that SSE inhibits tumor growth in vivo.
CONCLUSION: These results indicate that SSE inhibits proliferation and migration and induces apoptosis via ROS mediated inhibition of NF-κB signaling in renal cancer cells.

Keywords:  Migration; NF-κB; Proliferation; Renal Cancer; Sodium selenite

DOI:  https://doi.org/10.1186/s12885-022-09965-8
Cell Death Dis. 2022 Aug 06. 13(8): 685

shRNA‑mediated knockdown of KNTC1 inhibits non-small-cell lung cancer through regulating PSMB8.

Ruijun Liu, Ruili Liu, Zhiyi Guo, Jianghao Ren, Jia Huang, Qingquan Luo, Qiang Tan.

In view of the important roles played by Kinetochore proteins in mitosis, we believed that they may contribute to the development and progression of human cancers, which has been reported recently elsewhere. Kinetochore-associated 1 (KNTC1) participates in the segregation of sister chromatids during mitosis, the effects of which on non-small-cell lung cancer (NSCLC) remain unclear. Here, we sought to identify the biological significance of KNTC1 in NSCLC. KNTC1 protein expression in NSCLC tissues was investigated by immunohistochemistry. Lentivirus delivered short hairpin RNA (shRNA) was utilized to establish KNTC1 silence NSCLC cell lines. The effects of KNTC1 depletion on NSCLC cell proliferation, migration, apoptosis, and tumor formation were analyzed by MTT assay, wound-healing assay, transwell assay, flow cytometry assay, and in nude mouse models in vivo. After KNTC1 reduction, NSCLC cell viability, proliferation, migration, and invasion were restrained. A xenograft tumor model was also provided to demonstrate the inhibited tumorigenesis in NSCLC. In addition, the downstream mechanism analysis indicated that KNTC1 depletion was positively associated with PSMB8. The findings of the present study suggested that KNTC1 may have a pivotal role in mediating NSCLC progression and may act as a novel therapeutic target for NSCLC.

DOI: https://doi.org/10.1038/s41419-022-05140-w
Nat Cell Biol. 2022 Aug;24(8): 1239-1251

The MARCHF6 E3 ubiquitin ligase acts as an NADPH sensor for the regulation of ferroptosis.

Kha The Nguyen, Sang-Hyeon Mun, Jihye Yang, Jongeun Lee, Ok-Hee Seok, Eunjeong Kim, Dasom Kim, So Young An, Dong-Young Seo, Jeong-Yong Suh, Yoontae Lee, Cheol-Sang Hwang.

Ferroptosis is a unique form of cell death caused by excessive iron-dependent lipid peroxidation. The level of the anabolic reductant NADPH is a biomarker of ferroptosis sensitivity. However, specific regulators that detect cellular NADPH levels, thereby modulating downstream ferroptosis cascades, are largely unknown. We show here that the transmembrane endoplasmic reticulum MARCHF6 E3 ubiquitin ligase recognizes NADPH through its C-terminal regulatory region. This interaction upregulates the E3 ligase activity of MARCHF6, thus downregulating ferroptosis. We also found that MARCHF6 mediates the degradation of the key ferroptosis effectors ACSL4 and p53. Furthermore, inhibiting ferroptosis rescued the growth of MARCHF6-deficient tumours and peri-natal lethality of Marchf6-/- mice. Together, these findings identify MARCHF6 as a previously unknown NADPH sensor in the ubiquitin system and a crucial regulator of ferroptosis.

DOI: https://doi.org/10.1038/s41556-022-00973-1
Gen Physiol Biophys. 2022 Jul;41(4): 263-274

Induction of apoptosis through inactivation of ROS-dependent PI3K/Akt signaling pathway by platycodin D in human bladder urothelial carcinoma cells.

Cheol Park, Hee-Jae Cha, Hyesook Lee, Jin-Woo Jeong, MinHo Han, Kyoung Seob Song, Gi-Young Kim, Young-Chae Chang, Sun-Hee Leem, Jin Won Hyun, Heui-Soo Kim, Su Hyun Hong, Yung Hyun Choi.

Platycodin D (PD) is a triterpenoid saponin, a major bioactive constituent of the roots of Platycodon grandiflorum, which is well known for possessing various pharmacological properties. However, the anti-cancer mechanism of PD in bladder cancer cells remains poorly understood. In the current study, we investigated the effect of PD on the growth of human bladder urothelial carcinoma cells. PD treatment significantly reduced the cell survival of bladder cancer cells associated with induction of apoptosis and DNA damage. PD inhibited the expression of inhibitor of apoptosis family members, activated caspases, and induced cleavage of poly (ADP-ribose) polymerase. PD also increased the release of cytochrome c into the cytoplasm by disrupting the mitochondrial membrane potential while upregulating the expression ratio of Bax to Bcl-2. The PD-mediated anti-proliferative effect was significantly inhibited by pre-treatment with a pancaspase inhibitor, but not by an inhibitor of necroptosis. Moreover, PD suppressed the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway, and the apoptosis-inducing effect of PD was further enhanced by a PI3K inhibitor. In addition, PD increased the accumulation of reactive oxygen species (ROS), whereas N-acetyl cysteine (NAC), an ROS inhibitor, significantly attenuated the growth inhibition and inactivation of the PI3K/Akt/mTOR signaling caused by PD. Furthermore, NAC significantly suppressed apoptosis, DNA damage, and decreased cell viability induced by PD treatment. Collectively, our findings indicated that PD blocked the growth of bladder urothelial carcinoma cells by inducing ROS-mediated inactivation of the PI3K/Akt/mTOR signaling.

DOI: https://doi.org/10.4149/gpb_2022013
Cell Death Dis. 2022 Aug 09. 13(8): 697

CircKPNB1 mediates a positive feedback loop and promotes the malignant phenotypes of GSCs via TNF-α/NF-κB signaling.

Yang Jiang, Junshuang Zhao, Yingliang Liu, Juntao Hu, Liang Gao, Hui Wang, Daming Cui.

Glioma stem cells (GSCs) are a special kind of cells in GBM showing tumor initiation, self-renewal, and multi-lineage differentiation abilities. Finding novel circRNAs related to GSCs is of great significance for the study of glioma. qPCR, western blotting, and immunohistochemistry were used to detect the expression levels of circKPNB1, SPI1, DGCR8, and TNF-α. The expression of these molecules in GSCs was regulated by lentiviral-based infection. RNA immunoprecipitation assay, RNA pull-down, dual-luciferase reporter, and chromatin immunoprecipitation assays were used to study the direct regulation mechanisms among these molecules. All the MTS, EDU, transwell, neurosphere formation assays, ELDA assays, and xenograft experiments were used to detect the malignant phenotype of GSCs. We found a novel circRNA circKPNB1 was overexpressed in GBM and associated with GBM patients' poor prognosis. CircKPNB1 overexpression can promote the cell viabilities, proliferation, invasion, neurospheres formation abilities, and stemness of GSCs. Mechanistically, circKPNB1 regulates the protein stability and nuclear translocation of SPI1. SPI1 promotes the malignant phenotype of GSCs via TNF-α mediated NF-κB signaling. SPI1 can also transcriptionally upregulate DGCR8 expression, and the latter can maintain the stability of circKPNB1 and forms a positive feedback loop among DGCR8, circKPNB1 and SPI1. Our study found circKPNB1 was a novel oncogene in GBM and of great significance in the diagnosis and prognosis prediction of GBM and maybe a novel target for molecular targeted therapy.

DOI: https://doi.org/10.1038/s41419-022-05149-1
Nat Cell Biol. 2022 Aug;24(8): 1265-1277

A complex epigenome-splicing crosstalk governs epithelial-to-mesenchymal transition in metastasis and brain development.

Sanjeeb Kumar Sahu, Eneritz Agirre, Mohammed Inayatullah, Arun Mahesh, Neha Tiwari, Deborah P Lavin, Aditi Singh, Susanne Strand, Mustafa Diken, Reini F Luco, Juan Carlos Izpisua Belmonte, Vijay K Tiwari.

Epithelial-to-mesenchymal transition (EMT) renders epithelial cells migratory properties. While epigenetic and splicing changes have been implicated in EMT, the mechanisms governing their crosstalk remain poorly understood. Here we discovered that a C2H2 zinc finger protein, ZNF827, is strongly induced during various contexts of EMT, including in brain development and breast cancer metastasis, and is required for the molecular and phenotypic changes underlying EMT in these processes. Mechanistically, ZNF827 mediated these responses by orchestrating a large-scale remodelling of the splicing landscape by recruiting HDAC1 for epigenetic modulation of distinct genomic loci, thereby slowing RNA polymerase II progression and altering the splicing of genes encoding key EMT regulators in cis. Our findings reveal an unprecedented complexity of crosstalk between epigenetic landscape and splicing programme in governing EMT and identify ZNF827 as a master regulator coupling these processes during EMT in brain development and breast cancer metastasis.

DOI: https://doi.org/10.1038/s41556-022-00971-3
Int J Mol Sci. 2022 Jul 27. pii: 8282. [Epub ahead of print]23(15):

Dysregulation of SIRT3 SUMOylation Confers AML Chemoresistance via Controlling HES1-Dependent Fatty Acid Oxidation.

Yirong Zhang, Yajie Shen, Weiqing Wei, Wenhan Wang, Daiji Jiang, Yizhuo Ren, Zijing Peng, Qiuju Fan, Jinke Cheng, Jiao Ma.

  Sirtuin 3 (SIRT3) deacetylase is a key regulator for chemoresistance in acute myeloid leukemia (AML) cells due to its capability of modulating mitochondrial metabolism and reactive oxygen species (ROS). SIRT3 is de-SUMOylated by SUMO-specific peptidase 1 (SENP1), which enhances its deacetylase activity. Therefore, dysregulation of SIRT3 SUMOylation may lead to fortified chemoresistance in AML. Indeed, SIRT3 de-SUMOylation was induced by chemotherapeutic agents, which in turn, exacerbated resistance against chemotherapies in AML by activating SIRT3 via preventing its proteasome degradation. Furthermore, RNA-seq revealed that expression of a collection of genes was altered by SIRT3 de-SUMOylation including inhibition of transcription factor Hes Family BHLH Transcription Factor 1 (HES1), a downstream substrate of Notch1 signaling pathway, leading to increased fatty acids oxidation (FAO). Moreover, the SENP1 inhibitor momordin-Ic or HES1 overexpression synergized with cytarabine to eradicate AML cells in vitro and in xenograft mouse models. In summary, the current study revealed a novel role of SIRT3 SUMOylation in the regulation of chemoresistance in AML via HES1-dependent FAO and provided a rationale for SIRT3 SUMOylation and FAO targeted interventions to improve chemotherapies in AML.

Keywords:  AML chemoresistance; HES1; SIRT3 SUMOylation; fatty acid oxidation

DOI:  https://doi.org/10.3390/ijms23158282
Cell Death Dis. 2022 Aug 09. 13(8): 696

Genetic alterations of Keap1 confers chemotherapeutic resistance through functional activation of Nrf2 and Notch pathway in head and neck squamous cell carcinoma.

Syed S Islam, Khawlah Qassem, Shafiqul Islam, Rashed R Parag, Mohammed Z Rahman, Walid A Farhat, Herman Yeger, Abdelilah Aboussekhra, Bedri Karakas, Abu Shadat M Noman.

Keap1 mutations regulate Nrf2 activity and lead to chemoresistance in cancers. Yet the underlying molecular mechanisms of chemoresistance are poorly explored. By focusing and genotyping head and neck squamous cell carcinoma (HNSCC) that had available pathologic and clinical data, we provide evidence that Keap1 displays frequent alterations (17%) in HNSCC. Functional loss of Keap1 results in significant activation of Nrf2 and promotes cancer cell growth, proliferation, and elevated cancer stem cell (CSCs) self-renewal efficiency and resistance to oxidative stress. Furthermore, decreased Keap1 activity in these cells increased nuclear accumulation of Nrf2 and activation of the Notch pathway, causing enhanced transcriptional alterations of antioxidants, xenobiotic metabolism enzymes, and resistance to chemotherapeutic treatment. Limiting the Nrf2 activity by either Keap1 complementation or by Nrf2 silencing increased the sensitivity to chemotherapy in Keap1-mutated cells and repressed the CSC self-renewal activity. Our findings suggest that Keap1 mutations define a distinct disease phenotype and the Keap1-Nrf2 pathway is one of the leading molecular mechanisms for clinical chemotherapeutic resistance. Targeting this pathway may provide a potential and attractive personalized treatment strategy for overcoming chemotherapeutic resistance conferred by Keap1 mutations.

DOI: https://doi.org/10.1038/s41419-022-05126-8
Cancers (Basel). 2022 Jul 28. pii: 3684. [Epub ahead of print]14(15):

IKKε Inhibitor Amlexanox Promotes Olaparib Sensitivity through the C/EBP-β-Mediated Transcription of Rad51 in Castrate-Resistant Prostate Cancer.

Sophie Gilbert, Benjamin Péant, Anne-Marie Mes-Masson, Fred Saad.

  The progression of prostate cancer (PC) is often characterized by the development of castrate-resistant PC (CRPC). Patients with CRPC are treated with a variety of agents including new generation hormonal therapies or chemotherapy. However, as the cancer develops more resistance mechanisms, these drugs eventually become less effective and finding new therapeutic approaches is critical to improving patient outcomes. Previously, we have shown that IKKε depletion and IKKε inhibitors, BX795 and Amlexanox, decrease CRPC cell proliferation in vitro and in vivo and that IKKε inhibitors induce a senescence phenotype accompanied by increased DNA damage and genomic instability in CRPC cells. Here, we describe a new role for IKKε in DNA damage repair involving Rad51 and examine the therapeutic potential of Amlexanox combined with the PARP inhibitor Olaparib in CRPC cell lines. Combining Amlexanox with Olaparib decreased CRPC cell proliferation and enhanced DNA damage through the inhibition of Olaparib-induced Rad51 recruitment and expression in CRPC cells or IKKε-depleted PC-3 cells. We demonstrated that Rad51 promoter activity, measured by luciferase assay, was decreased with Amlexanox treatment or IKKε depletion and that Amlexanox treatment decreased the occupancy of transcription factor C/EBP-β on the Rad51 promoter. Our mouse model also showed that Amlexanox combined with Olaparib inhibited tumor growth of CRPC xenografts. Our study highlights a new role for IKKε in DNA damage repair through the regulation of Rad51 transcription and provides a rationale for the combination of Amlexanox and Olaparib in the treatment of patients with CRPC.

Keywords:  DNA damage; DNA damage repair; PARP inhibitors; combination therapy; transcription

DOI:  https://doi.org/10.3390/cancers14153684
J Biol Chem. 2022 Aug 06. pii: S0021-9258(22)00796-7. [Epub ahead of print] 102353

p38 MAPK-dependent phosphorylation of transcription factor SOX2 promotes an adaptive response to BRAF inhibitors in melanoma cells.

Silvia Pietrobono, Raffaella De Paolo, Domenico Mangiameli, Andrea Marranci, Ilaria Battisti, Cinzia Franchin, Giorgio Arrigoni, Davide Melisi, Laura Poliseno, Barbara Stecca.

  Despite recent advances in the development of BRAF kinase inhibitors (BRAFi) for BRAF-mutant melanomas, development of resistance remains a major clinical problem. In addition to genetic alterations associated with intrinsic resistance, several adaptive response mechanisms are known to be rapidly activated to allow cell survival in response to treatment, limiting efficacy. A better understanding of the mechanisms driving resistance is urgently needed to improve the success of BRAF-targeted therapies and to make therapeutic intervention more durable. In this study we identify the mitogen-activated protein kinase (MAPK) p38 as a novel mediator of the adaptive response of melanoma cells to BRAF-targeted therapy. Our findings demonstrate that BRAFi leads to an early increase in p38 activation, which promotes phosphorylation of the transcription factor SOX2 at Ser251, enhancing SOX2 stability, nuclear localization, and transcriptional activity. Furthermore, functional studies show that SOX2 depletion increases sensitivity of melanoma cells to BRAFi, whereas overexpression of a phosphomimetic SOX2-S251E mutant is sufficient to drive resistance and desensitize melanoma cells to BRAFi in vitro and in a Zebrafish xenograft model. We also found that SOX2 phosphorylation at serine 251 confers resistance to BRAFi by binding to the promoter and increasing transcriptional activation of the ATP-binding cassette (ABC) drug efflux transporter ABCG2. In summary, we unveil a p38/SOX2-mediated mechanism of adaptive response to BRAFi, which provides pro-survival signals to melanoma cells against the cytotoxic effects of BRAFi prior to acquiring resistance.

Keywords:  BRAF inhibitor; SOX2; drug resistance; p38 MAPK

DOI:  https://doi.org/10.1016/j.jbc.2022.102353
Mol Metab. 2022 Aug 06. pii: S2212-8778(22)00130-2. [Epub ahead of print] 101561

Histone lysine demethylase inhibition reprograms prostate cancer metabolism and mechanics.

Ugo Chianese, Chiara Papulino, Eugenia Passaro, Tom Mj Evers, Mehrad Babaei, Antonella Toraldo, Tommaso De Marchi, Emma Niméus, Vincenzo Carafa, Maria Maddalena Nicoletti, Nunzio Del Gaudio, Nunzia Iaccarino, Antonio Randazzo, Dante Rotili, Antonello Mai, Salvatore Cappabianca, Alireza Mashaghi, Fortunato Ciardiello, Lucia Altucci, Rosaria Benedetti.

   OBJECTIVE: Aberrant activity of androgen receptor (AR) is the primary cause underlying development and progression of prostate cancer (PCa) and castration-resistant PCa (CRPC). Androgen signaling regulates gene transcription and lipid metabolism, facilitating tumor growth and therapy resistance in early and advanced PCa. Although direct AR signaling inhibitors exist, AR expression and function can also be epigenetically regulated. Specifically, lysine (K)-specific demethylases (KDMs), which are often overexpressed in PCa and CRPC phenotypes, regulate the AR transcriptional program.
METHODS: We investigated LSD1/UTX inhibition, two KDMs, in PCa and CRPC using a multi-omics approach. We first performed a mitochondrial stress test to evaluate respiratory capacity after treatment with MC3324, a dual KDM-inhibitor, and then carried out lipidomic, proteomic, and metabolic analyses. We also investigated mechanical cellular properties with acoustic force spectroscopy.
RESULTS: MC3324 induced a global increase in H3K4me2 and H3K27me3 accompanied by significant growth arrest and apoptosis in androgen-responsive and -unresponsive PCa systems. LSD1/UTX inhibition downregulated AR at both transcriptional and non-transcriptional level, showing cancer selectivity, indicating its potential use in resistance to androgen deprivation therapy. Since MC3324 impaired metabolic activity, by modifying the protein and lipid content in PCa and CRPC cell lines. Epigenetic inhibition of LSD1/UTX disrupted mitochondrial ATP production and mediated lipid plasticity, which affected the phosphocholine class, an important structural element for the cell membrane in PCa and CRPC associated with changes in physical and mechanical properties of cancer cells.
CONCLUSIONS: Our data suggest a network in which epigenetics, hormone signaling, metabolite availability, lipid content, and mechano-metabolic process are closely related. This network may be able to identify additional hotspots for pharmacological intervention and underscores the key role of KDM-mediated epigenetic modulation in PCa and CRPC.

Keywords:  AR; KDMs; PCa; cell stiffness; lipid; metabolism

DOI:  https://doi.org/10.1016/j.molmet.2022.101561
Transl Lung Cancer Res. 2022 Jul;11(7): 1405-1419

BARX2/FOXA1/HK2 axis promotes lung adenocarcinoma progression and energy metabolism reprogramming.

Kai Xie, Jian Feng, Dingwei Fan, Shi Wang, Jing Luo, Zhijian Ren, Chao Zheng, Yifei Diao, Ramon Andrade De Mello, Simona Tavolari, Giovanni Brandi, Anja C Roden, Binhui Ren, Yi Shen, Lin Xu.

   Background: Metabolic reprogramming is an emerging cancer feature that has recently drawn special attention since it promotes tumor cell growth and proliferation. However, the mechanism of the Warburg effect is still largely unknown. This research aimed to reveal the effects of BarH-like homeobox 2 (BARX2) in regulating tumor progression and glucose metabolism in lung adenocarcinoma (LUAD).
Methods: Expression of BARX2 was measured by quantitative real-time polymerase chain reaction (qRT-PCR) in LUAD cell line and tissues, and the tumor-promoting function of BARX2 in LUAD cells was detected in vitro and in vivo xenograft models. The metabolic effects of BARX2 were examined by detecting glucose uptake, the production levels of lactate and pyruvate, and the extracellular acidification rate (ECAR). Chromatin immunoprecipitation (ChIP) assay and luciferase reporter gene assay were used to identify the underlying molecular mechanism of BARX2 regulation of HK2. Further studies showed that transcription factor FOXA1 directly interacts with BARX2 and promotes the transcriptional activity of BARX2.
Results: BARX2 was remarkably up-regulated in LUAD tissues and positively linked to advanced clinical stage and poor prognosis. In vitro and in vivo data indicated ectopic expression of BARX2 enhanced cell proliferation and tumorigenesis, whereas BARX2 knockdown suppressed these effects. Metabolic-related experiments showed BARX2 promoted the reprogramming of glucose metabolism. Mechanistically, the BARX2/FOXA1/HK2 axis promoted LUAD progression and energy metabolism reprogramming.
Conclusions: In summary, our research first defined BARX2 as a tumor-promoting factor in LUAD and that it may act as a novel prognostic biomarker and new therapeutic target for the disease.

Keywords:  BARX2; HK2; Transcription factor; glucose metabolism; lung adenocarcinoma (LUAD)

DOI:  https://doi.org/10.21037/tlcr-22-465
Int J Mol Sci. 2022 Aug 03. pii: 8644. [Epub ahead of print]23(15):

Isothiocyanates (ITCs) 1-(Isothiocyanatomethyl)-4-phenylbenzene and 1-Isothiocyanato-3,5-bis(trifluoromethyl)benzene-Aldehyde Dehydrogenase (ALDH) Inhibitors, Decreases Cisplatin Tolerance and Migratory Ability of NSCLC.

Jolanta Kryczka, Jakub Kryczka, Łukasz Janczewski, Anna Gajda, Andrzej Frączyk, Joanna Boncela, Beata Kolesińska, Ewa Brzeziańska-Lasota.

  One of the main treatment modalities for non-small-cell lung cancer (NSCLC) is cisplatin-based chemotherapy. However, the acquisition of cisplatin resistance remains a major problem. Existing chemotherapy regimens are often ineffective against cancer cells expressing aldehyde dehydrogenase (ALDH). As such, there is an urgent need for therapies targeting ALDH-positive cancer cells. The present study compares the anticancer properties of 36 structurally diverse isothiocyanates (ITCs) against NSCLC cells with the ALDH inhibitor disulfiram (DSF). Their potential affinity to ALDH isoforms and ABC proteins was assessed using AutoDockTools, allowing for selection of three compounds presenting the strongest affinity to all tested proteins. The selected ITCs had no impact on NSCLC cell viability (at tested concentrations), but significantly decreased the cisplatin tolerance of cisplatin-resistant variant of A549 (A549CisR) and advanced (stage 4) NSCLC cell line H1581. Furthermore, long-term supplementation with ITC 1-(isothiocyanatomethyl)-4-phenylbenzene reverses the EMT phenotype and migratory potential of A549CisR to the level presented by parental A549 cells, increasing E-Cadherin expression, followed by decreased expression of ABCC1 and ALDH3A1. Our data indicates that the ALDH inhibitors DSF and ITCs are potential adjuvants of cisplatin chemotherapy.

Keywords:  aldehyde dehydrogenase; cisplatin resistance; disulfiram; epithelial to mesenchymal transition; isothiocyanates; non-small-cell lung cancer

DOI:  https://doi.org/10.3390/ijms23158644
Int J Mol Sci. 2022 Aug 01. pii: 8528. [Epub ahead of print]23(15):

Polyploidy as an Adaptation against Loss of Heterozygosity in Cancer.

Marco Archetti.

  Polyploidy is common in cancer cells and has implications for tumor progression and resistance to therapies, but it is unclear whether it is an adaptation of the tumor or the non-adaptive effect of genomic instability. I discuss the possibility that polyploidy reduces the deleterious effects of loss of heterozygosity, which arises as a consequence of mitotic recombination, and which in diploid cells leads instead to the rapid loss of complementation of recessive deleterious mutations. I use computational predictions of loss of heterozygosity to show that a population of diploid cells dividing by mitosis with recombination can be easily invaded by mutant polyploid cells or cells that divide by endomitosis, which reduces loss of complementation, or by mutant cells that occasionally fuse, which restores heterozygosity. A similar selective advantage of polyploidy has been shown for the evolution of different types of asexual reproduction in nature. This provides an adaptive explanation for cyclical ploidy, mitotic slippage and cell fusion in cancer cells.

Keywords:  cancer; complementation; endomitosis; heterozygosity; polyploidy

DOI:  https://doi.org/10.3390/ijms23158528
Int J Radiat Biol. 2022 Aug 08. 1-47

Combination of PAKs inhibitors IPA-3 and PF-3758309 effectively suppresses colon carcinoma cell growth by perturbing DNA damage response.

Muzaffer Dukel, Kayahan Fıskın.

   PURPOSE: P21 protein (Cdc42/Rac)-activated kinase (PAK) is overexpressed in several tumors, including colon cancer, and plays a major role in cancer development and progression. PAKs proteins are speculated as new promising targets for cancer therapy due to their central role in many oncogenic pathways. Because PAKs proteins are very significant during carcinogenesis, we investigated the hypothesis that inhibition of PAKs with IPA-3 and PF-3758309 treatment could synergistically reduce colon carcinoma cell growth. Here, we aimed to understand whether both drugs were affecting colon cancer cell growth and their anticancer effects in colon cancer cells.
MATERIALS AND METHODS: The cytotoxic effects of both drugs were determined by a cell viability assay. Cell growth was determined via a soft agar colony formation test. Cell cycle and apoptosis were analyzed by flow cytometry. The effects of inhibitor drugs on marker genes of apoptosis, autophagy, cell cycle and DNA damage were tested via immunoblotting.
RESULTS AND CONCLUSIONS: We found out the synergistic effect of these drugs in pair on five colon cancer cell lines. Combined treatment with IPA-3 + PF-3758309 in SW620 and Colo 205 cells markedly suppressed colon formation and induced apoptosis, cell cycle arrest, and autophagy compared with treatment with each drug alone. Additionally, this combination sensitized colon cancer cells to ionizing radiation that resulted in inhibition of cell growth. Significance: Collectively, our findings show for the first time that cotreatment of IPA-3 with PF-3758309 exhibits superior inhibitory effects on colon carcinoma cell growth via inducing DNA damage-related cell death and also enforces a cell cycle arrest.

Keywords:  DNA damage; IPA-3; PF-3758309; apoptosis; autophagy; cell cycle

DOI:  https://doi.org/10.1080/09553002.2022.2110326
iScience. 2022 Aug 19. 25(8): 104752

Co-targeting of specific epigenetic regulators in combination with CDC7 potently inhibit melanoma growth.

Suresh Chava, Suresh Bugide, Parmanand Malvi, Romi Gupta.

  Melanoma is a highly aggressive skin cancer that frequently metastasizes, but current therapies only benefit some patients. Here, we demonstrate that the serine/threonine kinase cell division cycle 7 (CDC7) is overexpressed in melanoma, and patients with higher expression have shorter survival. Transcription factor ELK1 regulates CDC7 expression, and CDC7 inhibition promotes cell cycle arrest, senescence, and apoptosis, leading to inhibition of melanoma tumor growth and metastasis. Our chemical genetics screen with epigenetic inhibitors revealed stronger melanoma tumor growth inhibition when XL413 is combined with the EZH2 inhibitor GSK343 or BRPF1/2/3 inhibitor OF1. Mechanistically, XL413 with GSK343 or OF1 synergistically altered the expression of tumor-suppressive genes, leading to higher apoptosis than the single agent alone. Collectively, these results identify CDC7 as a driver of melanoma tumor growth and metastasis that can be targeted alone or in combination with EZH2 or BRPF1/2/3 inhibitors.

Keywords:  Cancer; Cell biology; Chemistry; Epigenetics

DOI:  https://doi.org/10.1016/j.isci.2022.104752
Cell Death Dis. 2022 Aug 06. 13(8): 689

Oxidative stress-mediated mitochondrial fission promotes hepatic stellate cell activation via stimulating oxidative phosphorylation.

Yanni Zhou, Dan Long, Ying Zhao, Shengfu Li, Yan Liang, Lin Wan, Jingyao Zhang, Fulai Xue, Li Feng.

Previous studies have demonstrated dysregulated mitochondrial dynamics in fibrotic livers and hepatocytes. Little is currently known about how mitochondrial dynamics are involved, nor is it clear how mitochondrial dynamics participate in hepatic stellate cell (HSC) activation. In the present study, we investigated the role of mitochondrial dynamics in HSC activation and the underlying mechanisms. We verified that mitochondrial fission was enhanced in human and mouse fibrotic livers and active HSCs. Moreover, increased mitochondrial fission driven by fis1 overexpression could promote HSC activation. Inhibiting mitochondrial fission using mitochondrial fission inhibitor-1 (Mdivi-1) could inhibit activation and induce apoptosis of active HSCs, indicating that increased mitochondrial fission is essential for HSC activation. Mdivi-1 treatment also induced apoptosis in active HSCs in vivo and thus ameliorated CCl4-induced liver fibrosis. We also found that oxidative phosphorylation (OxPhos) was increased in active HSCs, and OxPhos inhibitors inhibited activation and induced apoptosis in active HSCs. Moreover, increasing mitochondrial fission upregulated OxPhos, while inhibiting mitochondrial fission downregulated OxPhos, suggesting that mitochondrial fission stimulates OxPhos during HSC activation. Next, we found that inhibition of oxidative stress using mitoquinone mesylate (mitoQ) and Tempol inhibited mitochondrial fission and OxPhos and induced apoptosis in active HSCs, suggesting that oxidative stress contributes to excessive mitochondrial fission during HSC activation. In conclusion, our study revealed that oxidative stress contributes to enhanced mitochondrial fission, which triggers OxPhos during HSC activation. Importantly, inhibiting mitochondrial fission has huge prospects for alleviating liver fibrosis by eliminating active HSCs.

DOI: https://doi.org/10.1038/s41419-022-05088-x