bims-cadres 2022-07-31 papers

bims-cadres

Biomed News

on Cancer drug resistance

Issue of 2022–07–31
23 papers selected by
Rana Gbyli, Yale University

Diversity of the Origin of Cancer Stem Cells in Oral Squamous Cell Carcinoma and Its Clinical Implications.
Prostate Cancer Stem Cells: Clinical Aspects and Targeted Therapies.
Cancer stem cells and tumor heterogeneity: Deciphering the role in tumor progression and metastasis.
Epigenomic interplay in tumor heterogeneity: Potential of epidrugs as adjunct therapy.
Stearoyl-CoA desaturase 1 as a therapeutic target for cancer: a focus on hepatocellular carcinoma.
microRNA-497 prevents pancreatic cancer stem cell gemcitabine resistance, migration, and invasion by directly targeting nuclear factor kappa B 1.
HDAC Class I Inhibitor Domatinostat Preferentially Targets Glioma Stem Cells over Their Differentiated Progeny.
EGFR signaling activates intestinal stem cells by promoting mitochondrial biogenesis and β-oxidation.
JIB-04, a Pan-Inhibitor of Histone Demethylases, Targets Histone-Lysine-Demethylase-Dependent AKT Pathway, Leading to Cell Cycle Arrest and Inhibition of Cancer Stem-Like Cell Properties in Hepatocellular Carcinoma Cells.
Mitochondrial Elongation and OPA1 Play Crucial Roles during the Stemness Acquisition Process in Pancreatic Ductal Adenocarcinoma.
Targeting Replication Stress Response Pathways to Enhance Genotoxic Chemo- and Radiotherapy.
Hypoxia-regulated microRNAs: the molecular drivers of tumor progression.
Addiction of Cancer Stem Cells to MUC1-C in Triple-Negative Breast Cancer Progression.
A Novel ALDH1A1 Inhibitor Blocks Platinum-Induced Senescence and Stemness in Ovarian Cancer.
Reversal of cisplatin chemotherapy resistance by glutathione-resistant copper-based nanomedicine via cuproptosis.
Genetic, Metabolic and Immunological Features of Cancers with NRF2 Addiction.
Natural and synthetic compounds in Ovarian Cancer: A focus on NRF2/KEAP1 pathway.
Survivin Inhibition by Piperine Sensitizes Glioblastoma Cancer Stem Cells and Leads to Better Drug Response.
Antibladder Cancer Effects of Excavatolide C by Inducing Oxidative Stress, Apoptosis, and DNA Damage In Vitro.
N6-Methyladenosine RNA-Binding Protein YTHDF1 in Gastrointestinal Cancers: Function, Molecular Mechanism and Clinical Implication.
Lactate promotes metastasis of normoxic colorectal cancer stem cells through PGC-1α-mediated oxidative phosphorylation.
A Potent EGFR Inhibitor, N-Phenyl Pyrazoline Derivative Suppresses Aggressiveness and Cancer Stem Cell-Like Phenotype of Cervical Cancer Cells.
Cryptotanshinone suppresses tumorigenesis by inhibiting lipogenesis and promoting reactive oxygen species production in KRAS‑activated pancreatic cancer cells.

Cancers (Basel). 2022 Jul 22. pii: 3588. [Epub ahead of print]14(15):

Diversity of the Origin of Cancer Stem Cells in Oral Squamous Cell Carcinoma and Its Clinical Implications.

Chonji Fukumoto, Daisuke Uchida, Hitoshi Kawamata.

  Oral squamous cell carcinoma (OSCC) histopathologically accounts for ≥90% of oral cancer. Many clinicopathological risk factors for OSCC have also been proposed, and postoperative therapy is recommended in guidelines based on cancer stage and other risk factors. However, even if the standard treatment is provided according to the guidelines, a few cases rapidly recur or show cervical and distant metastasis. In this review article, we focus on the diversity of the origin of OSCC. We also discuss cancer stem cells (CSCs) as a key player to explain the malignancy of OSCC. CSCs are a subset of cancer cells that occupy a very small portion of the cancer mass and have characteristics of stem cells. When gene abnormalities accumulate in somatic stem cells, those cells transform into CSCs. CSCs as the origin of cancer then autonomously grow and develop into cancer. The histopathological phenotype of cancer cells is determined by the original characteristics of the somatic stem cells and/or surrounding environment. OSCC may be divided into the following three categories with different malignancy based on the origin of CSCs: cancer from oral epithelial stem cell-derived CSCs, cancer from stem cells in salivary gland-derived CSCs, and cancer from bone marrow-derived stem cell-derived CSCs.

Keywords:  bone marrow-derived stem cell; cancer stem cell; oral epithelial stem cell; oral squamous cell carcinoma; origin of cancer; somatic stem cell; stem cell

DOI:  https://doi.org/10.3390/cancers14153588
Front Oncol. 2022 ;12 935715

Prostate Cancer Stem Cells: Clinical Aspects and Targeted Therapies.

Isis Wolf, Christian Gratzke, Philipp Wolf.

  Despite decades of research and successful improvements in diagnosis and therapy, prostate cancer (PC) remains a major challenge. In recent years, it has become clear that PC stem cells (PCSCs) are the driving force in tumorigenesis, relapse, metastasis, and therapeutic resistance of PC. In this minireview, we discuss the impact of PCSCs in the clinical practice. Moreover, new therapeutic approaches to combat PCSCs are presented with the aim to achieve an improved outcome for patients with PC.

Keywords:  prostate cancer; prostate cancer stem cell antigens; prostate cancer stem cell hypothesis; prostate cancer stem cell therapy; prostate cancer stem cells

DOI:  https://doi.org/10.3389/fonc.2022.935715
Cytokine. 2022 Jul 21. pii: S1043-4666(22)00177-6. [Epub ahead of print]157 155968

Cancer stem cells and tumor heterogeneity: Deciphering the role in tumor progression and metastasis.

Upasana Kapoor-Narula, Nibedita Lenka.

  Tumor heterogeneity, in principle, reflects the variation among different cancer cell populations. It can be termed inter- or intra-tumoral heterogeneity, respectively, based on its occurrence in various tissues from diverse patients or within a single tumor. The intra-tumoral heterogeneity is one of the leading causes of cancer progression and treatment failure, with the cancer stem cells (CSCs) contributing immensely to the same. These niche cells, similar to normal stem cells, possess the characteristics of self-renewal and differentiation into multiple cell types. Moreover, CSCs contribute to tumor growth and surveillance by promoting recurrence, metastasis, and therapeutic resistance. Diverse factors, including intracellular signalling pathways and tumor microenvironment (TME), play a vital role in regulating these CSCs. Although a panel of markers is considered to identify the CSC pool in various cancers, further research is needed to discriminate cancer-specific CSC markers in those. CSCs have also been found to be promising therapeutic targets for cancer therapy. Several small molecules, natural compounds, antibodies, chimeric antigen receptor T (CAR-T) cells, and CAR-natural killer (CAR-NK) cells have emerged as therapeutic tools for specific targeting of CSCs. Interestingly, many of these are in clinical trials too. Despite being a much-explored avenue of research for years, and we have come to understand its nitty-gritty, there is still a tremendous gap in our knowledge concerning its precise genesis and regulation. Hence, a concrete understanding is needed to assess the CSC-TME link and how to target different cancer-specific CSCs by designing newer tools. In this review, we have summarized CSC, its causative, different pathways and factors regulating its growth, association with tumor heterogeneity, and last but not least, discussed many of the promising CSC-targeted therapies for combating cancer metastasis.

Keywords:  Cancer stem cells; Tumor heterogeneity; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.cyto.2022.155968
Cytokine. 2022 Jul 26. pii: S1043-4666(22)00176-4. [Epub ahead of print]157 155967

Epigenomic interplay in tumor heterogeneity: Potential of epidrugs as adjunct therapy.

Suvasmita Rath, Diptesh Chakraborty, Jyotsnarani Pradhan, Mohammad Imran Khan, Jagneshwar Dandapat.

  "Heterogeneity" in tumor mass has immense importance in cancer progression and therapy. The impact of tumor heterogeneity is an emerging field and not yet fully explored. Tumor heterogeneity is mainly considered as intra-tumor heterogeneity and inter-tumor heterogeneity based on their origin. Intra-tumor heterogeneity refers to the discrepancy within the same cancer mass while inter-tumor heterogeneity refers to the discrepancy between different patients having the same tumor type. Both of these heterogeneity types lead to variation in the histopathological as well as clinical properties of the cancer mass which drives disease resistance towards therapeutic approaches. Cancer stem cells (CSCs) act as pinnacle progenitors for heterogeneity development along with various other genetic and epigenetic parameters that are regulating this process. In recent times epigenetic factors are one of the most studied parameters that drive oxidative stress pathways essential during cancer progression. These epigenetic changes are modulated by various epidrugs and have an impact on tumor heterogeneity. The present review summarizes various aspects of epigenetic regulation in the tumor microenvironment, oxidative stress, and progression towards tumor heterogeneity that creates complications during cancer treatment. This review also explores the possible role of epidrugs in regulating tumor heterogeneity and personalized therapy against drug resistance.

Keywords:  Acetylation; Cancer stem cells; Epidrugs; Methylation; Reactive oxygen species; ncRNA

DOI:  https://doi.org/10.1016/j.cyto.2022.155967
Mol Biol Rep. 2022 Jul 29.

Stearoyl-CoA desaturase 1 as a therapeutic target for cancer: a focus on hepatocellular carcinoma.

Mortaza Raeisi, Leila Hassanbeigi, Fatemeh Khalili, Hengameh Kharrati-Shishavan, Mehdi Yousefi, Amir Mehdizadeh.

  One of the main characteristics of cancer cells is the alteration in lipid composition, which is associated with a significant monounsaturated fatty acids (MUFAs) enrichment. In addition to their structural functions in newly synthesized membranes in proliferating cancer cells, these fatty acids are involved in tumorigenic signaling. Increased expression and activity of stearoyl CoA desaturase (SCD1), i.e., an enzyme converting saturated fatty acids to Δ9-monounsaturated fatty acids, has been observed in various cancer cells. This increase in expression and activity has also been associated with cancer aggressiveness and poor patient outcome. Previous studies have also indicated the SCD1 involvement in increased cancer cells proliferation, growth, migration, epithelial to mesenchymal transition, metastasis, chemoresistance, and maintenance of cancer stem cells properties. Hence, SCD1 seems to be a player in malignancy development and may be considered a novel therapeutic target in cancers, including hepatocellular carcinoma (HCC). This review study aims to discuss the impact of SCD1 as a major component in lipid signaling in HCC.

Keywords:  Chemoresistance; Epithelial-to-mesenchymal transition; Hepatocellular carcinoma; MUFAs; SCD1

DOI:  https://doi.org/10.1007/s11033-021-07094-2
Aging (Albany NY). 2022 Jul 25. 14(undefined):

microRNA-497 prevents pancreatic cancer stem cell gemcitabine resistance, migration, and invasion by directly targeting nuclear factor kappa B 1.

Qiangfeng Yu, Zhe Xiu, Yizeng Jian, Jianyin Zhou, Xiaopeng Chen, Xiang Chen, Chunxiang Chen, Hongbao Chen, Sijia Yang, Libo Yin, Wenlong Zeng.

   OBJECTIVES: Cancer stem cells (CSCs) comprise a small population of cells in cancerous tumors and play a critical role in tumor resistance to chemotherapy. miRNAs have been reported to enhance the sensitivity of pancreatic cancer to chemotherapy. However, the underlying molecular mechanism requires better understanding.
METHODS: Cell viability and proliferation were examined with CCK8 assays. Quantitative real-time polymerase chain reaction was executed to assess mRNA expression. StarBase database was used to select the target genes of miRNA, which were further affirmed by dual luciferase assay. Transwell assay was used to analyze cell invasion and migration.
RESULTS: We proved that miR-497 could be obviously downregulated in pancreatic cancer tissues and CSCs from Aspc-1 and Bxpc-3 cells. In addition, inhibition of miR-497 evidently accelerated pancreatic CSC gemcitabine resistance, migration and invasion. Moreover, we revealed that nuclear factor kappa B 1 (NFκB1) was prominently upregulated in pancreatic cancer tissues and pancreatic CSCs, and NFκB1 was also identified as a direct target of miR-497. Furthermore, we demonstrated that overexpression of NFκB1 could also notably promote the viability, migration, and invasion of gemcitabine-treated pancreatic CSCs, but this effect could be partially abolished by miR-497 overexpression.
CONCLUSIONS: Those findings suggest that miR-497 overexpression could suppress gemcitabine resistance and the metastasis of pancreatic CSCs and non-CSCs by directly targeting NFκB1.

Keywords:  cancer stem cells; gemcitabine; microRNA-497; nuclear factor kappa B 1; pancreatic cancer

DOI:  https://doi.org/10.18632/aging.204193
Int J Mol Sci. 2022 Jul 22. pii: 8084. [Epub ahead of print]23(15):

HDAC Class I Inhibitor Domatinostat Preferentially Targets Glioma Stem Cells over Their Differentiated Progeny.

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

  Cancer stem cells (CSCs) are in general characterized by higher resistance to cell death and cancer therapies than non-stem differentiated cancer cells. However, we and others have recently revealed using glioma stem cells (GSCs) as a model that, unexpectedly, CSCs have specific vulnerabilities that make them more sensitive to certain drugs compared with their differentiated counterparts. We aimed in this study to discover novel drugs targeting such Achilles' heels of GSCs as anti-GSC drug candidates to be used for the treatment of glioblastoma, the most therapy-resistant form of brain tumors. Here we report that domatinostat (4SC-202), a class I HDAC inhibitor, is one such candidate. At concentrations where it showed no or minimal growth inhibitory effect on differentiated GSCs and normal cells, domatinostat effectively inhibited the growth of GSCs mainly by inducing apoptosis. Furthermore, GSCs that survived domatinostat treatment lost their self-renewal capacity. These results suggested that domatinostat is a unique drug that selectively eliminates GSCs not only physically by inducing cell death but also functionally by inhibiting their self-renewal. Our findings also imply that class I HDACs and/or LSD1, another target of domatinostat, may possibly have a specific role in the maintenance of GSCs and therefore could be an attractive target in the development of anti-GSC therapies.

Keywords:  epigenetic modulation; glioma initiating cell; stemness; tumor initiating cell

DOI:  https://doi.org/10.3390/ijms23158084
Curr Biol. 2022 Jul 19. pii: S0960-9822(22)01104-6. [Epub ahead of print]

EGFR signaling activates intestinal stem cells by promoting mitochondrial biogenesis and β-oxidation.

Chenge Zhang, Yinhua Jin, Marco Marchetti, Mitchell R Lewis, Omar T Hammouda, Bruce A Edgar.

  EGFR-RAS-ERK signaling promotes growth and proliferation in many cell types, and genetic hyperactivation of RAS-ERK signaling drives many cancers. Yet, despite intensive study of upstream components in EGFR signal transduction, the identities and functions of downstream effectors in the pathway are poorly understood. In Drosophila intestinal stem cells (ISCs), the transcriptional repressor Capicua (Cic) and its targets, the ETS-type transcriptional activators Pointed (pnt) and Ets21C, are essential downstream effectors of mitogenic EGFR signaling. Here, we show that these factors promote EGFR-dependent metabolic changes that increase ISC mass, mitochondrial growth, and mitochondrial activity. Gene target analysis using RNA and DamID sequencing revealed that Pnt and Ets21C directly upregulate not only DNA replication and cell cycle genes but also genes for oxidative phosphorylation, the TCA cycle, and fatty acid beta-oxidation. Metabolite analysis substantiated these metabolic functions. The mitochondrial transcription factor B2 (mtTFB2), a direct target of Pnt, was required and partially sufficient for EGFR-driven ISC growth, mitochondrial biogenesis, and proliferation. MEK-dependent EGF signaling stimulated mitochondrial biogenesis in human RPE-1 cells, indicating the conservation of these metabolic effects. This work illustrates how EGFR signaling alters metabolism to coordinately activate cell growth and cell division.

Keywords:  Ets21C; ISC; Pointed; intestinal stem cell; mitochondrial biogenesis; mtTFB2; proliferation

DOI:  https://doi.org/10.1016/j.cub.2022.07.003
Int J Mol Sci. 2022 Jul 11. pii: 7657. [Epub ahead of print]23(14):

JIB-04, a Pan-Inhibitor of Histone Demethylases, Targets Histone-Lysine-Demethylase-Dependent AKT Pathway, Leading to Cell Cycle Arrest and Inhibition of Cancer Stem-Like Cell Properties in Hepatocellular Carcinoma Cells.

Jina Lee, Ji-Soo Kim, Hye-In Cho, So-Ra Jo, Yeun-Kyu Jang.

  JIB-04, a pan-histone lysine demethylase (KDM) inhibitor, targets drug-resistant cells, along with colorectal cancer stem cells (CSCs), which are crucial for cancer recurrence and metastasis. Despite the advances in CSC biology, the effect of JIB-04 on liver CSCs (LCSCs) and the malignancy of hepatocellular carcinoma (HCC) has not been elucidated yet. Here, we showed that JIB-04 targeted KDMs, leading to the growth inhibition and cell cycle arrest of HCC, and abolished the viability of LCSCs. JIB-04 significantly attenuated CSC tumorsphere formation, growth, relapse, migration, and invasion in vitro. Among KDMs, the deficiency of KDM4B, KDM4D, and KDM6B reduced the viability of the tumorspheres, suggesting their roles in the function of LCSCs. RNA sequencing revealed that JIB-04 affected various cancer-related pathways, especially the PI3K/AKT pathway, which is crucial for HCC malignancy and the maintenance of LCSCs. Our results revealed KDM6B-dependent AKT2 expression and the downregulation of E2F-regulated genes via JIB-04-induced inhibition of the AKT2/FOXO3a/p21/RB axis. A ChIP assay demonstrated JIB-04-induced reduction in H3K27me3 at the AKT2 promoter and the enrichment of KDM6B within this promoter. Overall, our results strongly suggest that the inhibitory effect of JIB-04 on HCC malignancy and the maintenance of LCSCs is mediated via targeting the KDM6B-AKT2 pathway, indicating the therapeutic potential of JIB-04.

Keywords:  AKT2; AKT2/FOXO3a/p21/RB axis; JIB-04; cancer stem cells; cell cycle arrest; hepatocellular carcinoma; histone lysine demethylase inhibitor; histone lysine demethylases (KDMs)

DOI:  https://doi.org/10.3390/ijms23147657
Cancers (Basel). 2022 Jul 14. pii: 3432. [Epub ahead of print]14(14):

Mitochondrial Elongation and OPA1 Play Crucial Roles during the Stemness Acquisition Process in Pancreatic Ductal Adenocarcinoma.

Cristian Andres Carmona-Carmona, Elisa Dalla Pozza, Giulia Ambrosini, Barbara Cisterna, Marta Palmieri, Ilaria Decimo, José M Cuezva, Emanuela Bottani, Ilaria Dando.

  Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer with an overall 5-year survival rate of less than 9%. The high aggressiveness of PDAC is linked to the presence of a subpopulation of cancer cells with a greater tumorigenic capacity, generically called cancer stem cells (CSCs). CSCs present a heterogeneous metabolic profile that might be supported by an adaptation of mitochondrial function; however, the role of this organelle in the development and maintenance of CSCs remains controversial. To determine the role of mitochondria in CSCs over longer periods, which may reflect more accurately their quiescent state, we studied the mitochondrial physiology in CSCs at short-, medium-, and long-term culture periods. We found that CSCs show a significant increase in mitochondrial mass, more mitochondrial fusion, and higher mRNA expression of genes involved in mitochondrial biogenesis than parental cells. These changes are accompanied by a regulation of the activities of OXPHOS complexes II and IV. Furthermore, the protein OPA1, which is involved in mitochondrial dynamics, is overexpressed in CSCs and modulates the tumorsphere formation. Our findings indicate that CSCs undergo mitochondrial remodeling during the stemness acquisition process, which could be exploited as a promising therapeutic target against pancreatic CSCs.

Keywords:  OPA1; cancer stem cells; mitochondrial dynamics; mitochondrial fusion; pancreatic ductal adenocarcinoma

DOI:  https://doi.org/10.3390/cancers14143432
Molecules. 2022 Jul 25. pii: 4736. [Epub ahead of print]27(15):

Targeting Replication Stress Response Pathways to Enhance Genotoxic Chemo- and Radiotherapy.

Jac A Nickoloff.

  Proliferating cells regularly experience replication stress caused by spontaneous DNA damage that results from endogenous reactive oxygen species (ROS), DNA sequences that can assume secondary and tertiary structures, and collisions between opposing transcription and replication machineries. Cancer cells face additional replication stress, including oncogenic stress that results from the dysregulation of fork progression and origin firing, and from DNA damage induced by radiotherapy and most cancer chemotherapeutic agents. Cells respond to such stress by activating a complex network of sensor, signaling and effector pathways that protect genome integrity. These responses include slowing or stopping active replication forks, protecting stalled replication forks from collapse, preventing late origin replication firing, stimulating DNA repair pathways that promote the repair and restart of stalled or collapsed replication forks, and activating dormant origins to rescue adjacent stressed forks. Currently, most cancer patients are treated with genotoxic chemotherapeutics and/or ionizing radiation, and cancer cells can gain resistance to the resulting replication stress by activating pro-survival replication stress pathways. Thus, there has been substantial effort to develop small molecule inhibitors of key replication stress proteins to enhance tumor cell killing by these agents. Replication stress targets include ATR, the master kinase that regulates both normal replication and replication stress responses; the downstream signaling kinase Chk1; nucleases that process stressed replication forks (MUS81, EEPD1, Metnase); the homologous recombination catalyst RAD51; and other factors including ATM, DNA-PKcs, and PARP1. This review provides an overview of replication stress response pathways and discusses recent pre-clinical studies and clinical trials aimed at improving cancer therapy by targeting replication stress response factors.

Keywords:  DNA damage response; DNA replication stress; genotoxic cancer therapy; oncogenic stress; targeted therapy

DOI:  https://doi.org/10.3390/molecules27154736
Crit Rev Biochem Mol Biol. 2022 Jul 28. 1-26

Hypoxia-regulated microRNAs: the molecular drivers of tumor progression.

Sakunie Sawai, Pooi-Fong Wong, Thamil Selvee Ramasamy.

  Hypoxia is a common feature of the tumor microenvironment (TME) of nearly all solid tumors, leading to therapeutic failure. The changes in stiffness of the extracellular matrix (ECM), pH gradients, and chemical balance that contribute to multiple cancer hallmarks are closely regulated by intratumoral oxygen tension via its primary mediators, hypoxia-inducible factors (HIFs). HIFs, especially HIF-1α, influence these changes in the TME by regulating vital cancer-associated signaling pathways and cellular processes including MAPK/ERK, NF-κB, STAT3, PI3K/Akt, Wnt, p53, and glycolysis. Interestingly, research has revealed the involvement of epigenetic regulation by hypoxia-regulated microRNAs (HRMs) of downstream target genes involved in these signaling. Through literature search and analysis, we identified 48 HRMs that have a functional role in the regulation of 5 key cellular processes: proliferation, metabolism, survival, invasion and migration, and immunoregulation in various cancers in hypoxic condition. Among these HRMs, 17 were identified to be directly associated with HIFs which include miR-135b, miR-145, miR-155, miR-181a, miR-182, miR-210, miR-224, miR-301a, and miR-675-5p as oncomiRNAs, and miR-100-5p, miR-138, miR-138-5p, miR-153, miR-22, miR-338-3p, miR-519d-3p, and miR-548an as tumor suppressor miRNAs. These HRMs serve as a potential lead in the development of miRNA-based targeted therapy for advanced solid tumors. Future development of combined HIF-targeted and miRNA-targeted therapy is possible, which requires comprehensive profiling of HIFs-HRMs regulatory network, and improved formula of the delivery vehicles to enhance the therapeutic kinetics of the targeted cancer therapy (TCT) moving forward.

Keywords:  Hypoxia; cancer stem cells (CSCs); cell survival; metabolic reprogramming; miRNA-based targeted therapy; microRNAs; resistance; tumor progression

DOI:  https://doi.org/10.1080/10409238.2022.2088684
Int J Mol Sci. 2022 Jul 26. pii: 8219. [Epub ahead of print]23(15):

Addiction of Cancer Stem Cells to MUC1-C in Triple-Negative Breast Cancer Progression.

Nami Yamashita, Donald Kufe.

  Triple-negative breast cancer (TNBC) is an aggressive malignancy with limited treatment options. TNBC progression is associated with expansion of cancer stem cells (CSCs). Few insights are available regarding druggable targets that drive the TNBC CSC state. This review summarizes the literature on TNBC CSCs and the compelling evidence that they are addicted to the MUC1-C transmembrane protein. In normal epithelia, MUC1-C is activated by loss of homeostasis and induces reversible wound-healing responses of inflammation and repair. However, in settings of chronic inflammation, MUC1-C promotes carcinogenesis. MUC1-C induces EMT, epigenetic reprogramming and chromatin remodeling in TNBC CSCs, which are dependent on MUC1-C for self-renewal and tumorigenicity. MUC1-C-induced lineage plasticity in TNBC CSCs confers DNA damage resistance and immune evasion by chronic activation of inflammatory pathways and global changes in chromatin architecture. Of therapeutic significance, an antibody generated against the MUC1-C extracellular domain has been advanced in a clinical trial of anti-MUC1-C CAR T cells and in IND-enabling studies for development as an antibody-drug conjugate (ADC). Agents targeting the MUC1-C cytoplasmic domain have also entered the clinic and are undergoing further development as candidates for advancing TNBC treatment. Eliminating TNBC CSCs will be necessary for curing this recalcitrant cancer and MUC1-C represents a promising druggable target for achieving that goal.

Keywords:  CSC; DNA damage resistance; MUC1-C; TNBC; immune evasion

DOI:  https://doi.org/10.3390/ijms23158219
Cancers (Basel). 2022 Jul 15. pii: 3437. [Epub ahead of print]14(14):

A Novel ALDH1A1 Inhibitor Blocks Platinum-Induced Senescence and Stemness in Ovarian Cancer.

Vaishnavi Muralikrishnan, Fang Fang, Tyler C Given, Ram Podicheti, Mikhail Chtcherbinine, Tara X Metcalfe, Shruthi Sriramkumar, Heather M O'Hagan, Thomas D Hurley, Kenneth P Nephew.

  Ovarian cancer is a deadly disease attributed to late-stage detection as well as recurrence and the development of chemoresistance. Ovarian cancer stem cells (OCSCs) are hypothesized to be largely responsible for the emergence of chemoresistant tumors. Although chemotherapy may initially succeed at decreasing the size and number of tumors, it leaves behind residual malignant OCSCs. In this study, we demonstrate that aldehyde dehydrogenase 1A1 (ALDH1A1) is essential for the survival of OCSCs. We identified a first-in-class ALDH1A1 inhibitor, compound 974, and used 974 as a tool to decipher the mechanism of stemness regulation by ALDH1A1. The treatment of OCSCs with 974 significantly inhibited ALDH activity, the expression of stemness genes, and spheroid and colony formation. An in vivo limiting dilution assay demonstrated that 974 significantly inhibited CSC frequency. A transcriptomic sequencing of cells treated with 974 revealed a significant downregulation of genes related to stemness and chemoresistance as well as senescence and the senescence-associated secretory phenotype (SASP). We confirmed that 974 inhibited the senescence and stemness induced by platinum-based chemotherapy in functional assays. Overall, these data establish that ALDH1A1 is essential for OCSC survival and that ALDH1A1 inhibition suppresses chemotherapy-induced senescence and stemness. Targeting ALDH1A1 using small-molecule inhibitors in combination with chemotherapy therefore presents a promising strategy to prevent ovarian cancer recurrence and has the potential for clinical translation.

Keywords:  ALDH1A1; cancer stem cells; chemotherapy resistance; ovarian cancer; senescence

DOI:  https://doi.org/10.3390/cancers14143437
J Mater Chem B. 2022 Jul 29.

Reversal of cisplatin chemotherapy resistance by glutathione-resistant copper-based nanomedicine via cuproptosis.

Yao Lu, Qingqing Pan, Wenxia Gao, Yuji Pu, Bin He.

Platinum-based chemotherapy is widely used to treat various cancers. However, exogenous platinum is likely to cause severe side effects and drug resistance induced by upregulated glutathione (GSH) in cancer cells poses a threat to the management of cancer progression and recurrence. Anticancer copper-organic complexes are excellent candidates to substitute platinum-based chemotherapeutics, exhibiting lower systemic toxicity and even overcoming platinum-based chemotherapy resistance. Here, we report the GSH-resistance of copper(II) bis(diethyldithiocarbamate) (CuET) and its reversal of cisplatin resistance in non-small-cell lung cancer via cuproptosis. Electrochemistry and UV-vis spectroscopy studies demonstrate that CuET possesses a lower reduction potential and the reaction inertness with GSH. Importantly, CuET overcomes the drug resistance of A549/DDP cells and the anticancer effect is hardly affected by intracellular GSH levels. To improve the solubility and bioavailability, bovine serum albumin-stabilized CuET nanoparticles (NPs) are prepared and they have a high drug loading content of 27.5% and excellent physiological stability. In vitro studies manifest that CuET NPs augment the distributions in the cytosol and cytoskeleton, inducing cell death via cuproptosis in A549/DDP cells, which is distinctly different from the apoptosis pattern induced by cisplatin. In vivo antitumor evaluation shows that the nanomedicine has superior biosafety and potent antitumor activity in a cisplatin-resistant tumor model. Our study suggests that copper-organic complex-based nanosystems could be a powerful toolbox to tackle the platinum-based drug resistance and systemic toxicity concerns.

DOI: https://doi.org/10.1039/d2tb01150f
FEBS Lett. 2022 Jul 27.

Genetic, Metabolic and Immunological Features of Cancers with NRF2 Addiction.

Hiroshi Kitamura, Haruna Takeda, Hozumi Motohashi.

  Nuclear factor erythroid-derived 2-like 2 (NRF2) is a master transcription factor that coordinately regulates the expression of many cytoprotective genes and plays a central role in defense mechanisms against oxidative and electrophilic insults. Although increased NRF2 activity is principally beneficial for our health, NRF2 activation in cancer cells is detrimental. Many human cancers exhibit persistent NRF2 activation and such cancer cells rely on NRF2 for most of their malignant characteristics, such as therapeutic resistance and aggressive tumorigenesis, and thus fall into NRF2 addiction. The persistent activation of NRF2 confers great advantages on cancer cells, whereas it is not tolerated by normal cells, suggesting that certain requirements are necessary for a cell to exploit NRF2 and evolve into malignant a cancer cell. In this review, recent reports and data on the genetic, metabolic and immunological features of NRF2-activated cancer cells are summarized, and prerequisites for NRF2 addiction in cancer cells and their therapeutic applications are discussed.

Keywords:  CEBPB; KEAP1; NOTCH3; NRF2; cancer stemness; immunoevasion; malignancy; metabolic reprogramming; non-small cell lung cancer; pentose phosphate pathway

DOI:  https://doi.org/10.1002/1873-3468.14458
Pharmacol Res. 2022 Jul 25. pii: S1043-6618(22)00310-3. [Epub ahead of print]183 106365

Natural and synthetic compounds in Ovarian Cancer: A focus on NRF2/KEAP1 pathway.

Giovanni Tossetta, Daniela Marzioni.

  Among gynecologic malignancies, ovarian cancer is one of the most dangerous, with a high fatality rate and relapse due to the occurrence of chemoresistance. Many researchers demonstrated that oxidative stress is involved in tumor occurrence, development and procession. Nuclear factor erythroid 2-related factor 2 (NRF2) is an important transcription factor playing an important role in protecting against oxidative damage. Increased levels of Reactive Oxygen Species (ROS) activate NRF2 signaling inducing the expression of antioxidant enzymes such as heme oxygenase (HO-1), catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD) that protect cells against oxidative stress. However, NRF2 activation in cancer cells is responsible for the development of chemoresistance inactivating drug-mediated oxidative stress that normally leads cancer cells to death. In this review we analyzed the current literature regarding the role of natural and synthetic compounds in modulating NRF2/KEAP1 (Kelch Like ECH Associated Protein 1) pathway in in vitro models of ovarian cancer. In particular, we reported how these compounds can modulate chemotherapy response.

Keywords:  Ailanthone (PubChem CID: 72965); Apatinib (PubChem CID: 11315474); Chemotherapy; Cisplatin; Clofibrate (PubChem CID: 2796); Compounds; Dexamethasone (PubChem CID: 5743); Diosmetin (PubChem CID: 5281612); Erastin (PubChem CID: 11214940); Genistein (PubChem CID: 5280961); Luteolin (PubChem CID: 5280445); NRF2; Ovarian Cancer; RRx-001 (PubChem CID: 15950826); Signaling; Sulforaphane (PubChem CID: 5350)

DOI:  https://doi.org/10.1016/j.phrs.2022.106365
Int J Mol Sci. 2022 Jul 09. pii: 7604. [Epub ahead of print]23(14):

Survivin Inhibition by Piperine Sensitizes Glioblastoma Cancer Stem Cells and Leads to Better Drug Response.

Neerada Meenakshi Warrier, Ramesh Kumar Krishnan, Vijendra Prabhu, Raghu Chandrashekhar Hariharapura, Prasoon Agarwal, Praveen Kumar.

  Glioblastoma multiforme (GBM) cancer stem cells (GSCs) are one of the strongest contributing factors to treatment resistance in GBM. Identification of biomarkers capable of directly affecting these cells within the bulk tumor is a major challenge associated with the development of new targeting strategies. In this study, we focus on understanding the potential of the multifunctional extraordinaire survivin as a biomarker for GSCs. We analyzed the expression profiles of this gene using various publicly available datasets to understand its importance in stemness and other cancer processes. The findings from these studies were further validated using human GSCs isolated from a GBM cell line. In these GSCs, survivin was inhibited using the dietary phytochemical piperine (PIP) and the subsequent effects on stemness, cancer processes and Temozolomide were investigated. In silico analysis identified survivin to be one of the most significant differentially regulated gene in GSCs, in comparison to common stemness markers. Further validation studies on the isolated GSCs showed the importance of survivin in stemness, cancer progression and therapy resistance. Taken together, our study identifies survivin as a more consistent GSC marker and also suggests the possibility of using survivin inhibitors along with standard of care drugs for better therapeutic outcomes.

Keywords:  glioblastoma cancer stem cells; integrative analysis; piperine; survivin; temozolomide; therapeutic targeting

DOI:  https://doi.org/10.3390/ijms23147604
Pharmaceuticals (Basel). 2022 Jul 24. pii: 917. [Epub ahead of print]15(8):

Antibladder Cancer Effects of Excavatolide C by Inducing Oxidative Stress, Apoptosis, and DNA Damage In Vitro.

Che-Wei Yang, Tsu-Ming Chien, Chia-Hung Yen, Wen-Jeng Wu, Jyh-Horng Sheu, Hsueh-Wei Chang.

  Excavatolide C (EXCC) is a bioactive compound derived from the gorgonian octocoral Briareum excavatum, and its anticancer effects are rarely addressed, particularly for bladder cancer. This investigation aimed to explore the potential impacts of EXCC on inhibiting the proliferation of three kinds of bladder cancer cells (5637, BFTC905, and T24). EXCC inhibits bladder cancer cell proliferation based on 48 h ATP assay. This antiproliferation function is validated to be oxidative stress dependent. Cellular and mitochondrial oxidative stresses were upregulated by EXCC, accompanied by depleting glutathione and mitochondrial membrane potential. These antiproliferation and oxidative stress events were suppressed by N-acetylcysteine (NAC), indicating that EXCC has an oxidative stress-regulating function for antiproliferation of bladder cancer cells. Oxidative stress-related responses such as apoptosis, caspase activation, and DNA damage were upregulated by EXCC and reverted by NAC. Taken together, the antiproliferation function of EXCC provides a potential treatment against bladder cancer cells via oxidative stress modulation.

Keywords:  DNA damage; apoptosis; bladder cancer; oxidative stress; soft coral

DOI:  https://doi.org/10.3390/ph15080917
Cancers (Basel). 2022 Jul 18. pii: 3489. [Epub ahead of print]14(14):

N6-Methyladenosine RNA-Binding Protein YTHDF1 in Gastrointestinal Cancers: Function, Molecular Mechanism and Clinical Implication.

Danyu Chen, Henley Cheung, Harry Cheuk-Hay Lau, Jun Yu, Chi Chun Wong.

  N6-methyladenosine (m6A) is the most abundant internal modification in eukaryotic cell mRNA, and this modification plays a key role in regulating mRNA translation, splicing, and stability. Emerging evidence implicates aberrant m6A as a crucial player in the occurrence and development of diseases, especially GI cancers. Among m6A regulators, YTHDF1 is the most abundant m6A reader that functionally connects m6A-modified mRNA to its eventual fate, mostly notably protein translation. Here, we summarized the function, molecular mechanisms, and clinical implications of YTHDF1 in GI cancers. YTHDF1 is largely upregulated in multiple GI cancer and its high expression predicts poor patient survival. In vitro and in vivo experimental evidence largely supports the role of YTDHF1 in promoting cancer initiation, progression, and metastasis, which suggests the oncogenic function of YTHDF1 in GI cancers. Besides, YTHDF1 overexpression is associated with changes in the tumor microenvironment that are favorable to tumorigenesis. Mechanistically, YTHDF1 regulates the expression of target genes by promoting translation, thereby participating in cancer-related signaling pathways. Targeting YTHDF1 holds therapeutic potential, as the overexpression of YTHDF1 is associated with tumor resistance to chemotherapy and immunotherapy. In summary, YTHDF1-mediated regulation of m6A modified mRNA is an actionable target and a prognostic factor for GI cancers.

Keywords:  N6-methyladenosine; YTHDF1; colorectal cancer; drug resistance; gastric cancer; gastrointestinal cancer; immunotherapy; liver cancer; oncogenic signaling

DOI:  https://doi.org/10.3390/cancers14143489
Cell Death Dis. 2022 Jul 27. 13(7): 651

Lactate promotes metastasis of normoxic colorectal cancer stem cells through PGC-1α-mediated oxidative phosphorylation.

Shuang Liu, Hui Zhao, Yibing Hu, Chang Yan, Yulong Mi, Xiaolan Li, Deding Tao, Jichao Qin.

Uneven oxygen supply in solid tumors leads to hypoxic and normoxic regions. Hypoxic cells exhibit increased secretion of lactate, which creates an acidic tumor microenvironment (TME). This acidic TME is positively associated with tumor metastasis. Despite the increased metastatic capacity of hypoxic cells, they are located relatively further away from the blood vessels and have limited access to the circulatory system. Studies have shown that cancer stem cells (CSCs) are enriched for tumor metastasis-initiating cells and generally undergo aerobic respiration, which could be enhanced by lactate. We therefore hypothesized that TME-derived lactate may promote the metastasis of normoxic CSCs. In the present study, the abundance of hypoxic and normoxic CSCs was analyzed in primary CRC tumors. It was found that the proportion of normoxic CSCs was positively associated with tumor stage. Using two human CRC cell lines, LoVo and SW480, and a patient-derived xenograft (XhCRC), it was found that treatment with lactate promoted normoxic CSC metastasis. Metabolism analysis indicated that, upon treatment with lactate, oxidative phosphorylation (OXPHOS) activity in normoxic CSCs was enhanced, whereas hypoxic CSCs were rarely altered. At the molecular level, the expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), a master regulator of lactate oxidation, was found to be elevated in normoxic CSCs. Furthermore, PGC-1α knockdown markedly reduced the metastatic potential of normoxic CSCs. Notably, both the PGC-1α-mediated OXPHOS activity and metastatic potential were impaired when hypoxia-inducible factor-1α (HIF-1α) was activated in normoxic CSCs. Together, these findings provide a therapeutic strategy against tumor metastasis through the targeting of PGC-1α and, thus, the suppression of lactate-feeding OXPHOS in normoxic CSCs may improve the therapeutic benefit of patients with cancer, particularly CRC.

DOI: https://doi.org/10.1038/s41419-022-05111-1
Drug Des Devel Ther. 2022 ;16 2325-2339

A Potent EGFR Inhibitor, N-Phenyl Pyrazoline Derivative Suppresses Aggressiveness and Cancer Stem Cell-Like Phenotype of Cervical Cancer Cells.

Mustofa, Pamungkas Bagus Satriyo, Artania Adnin Tri Suma, Stephanus Satria Wira Waskitha, Tutik Dwi Wahyuningsih, Eti Nurwening Sholikhah.

   Objective: Metastasis causes approximately 90% of cancer-related deaths, including in cervical cancer patients. Uncontrolled cell proliferation, migration, and cancer stemness act as critical events in primary tumor growth and cancer metastasis progression in cervical cancer. Here, we investigated the anti-proliferative, anti-migration, and cancer stemness inhibition activity of N-phenyl pyrazoline derivatives against cervical cancer cells.
Methods: The chalcone and phenylhydrazine were used to synthesize the N-phenyl pyrazoline 2/5 (P2 and P5). The MTT, colony formation, and wound healing assays were performed to evaluate the N-phenyl pyrazoline effect in HeLa cells. The N-phenyl pyrazoline's protein target was predicted using SwissTargetPrediction and AutoDock Vina software. The Western blotting assay was performed to evaluate the target proteins. The public dataset analysis was used to confirm the clinical relevance of target protein in cervical cancer patients.
Results: N-phenyl pyrazoline 2 and 5 were successfully synthesized. The N-phenyl pyrazolines 2 and 5 exhibit cytotoxic effect in HeLa cell line with 20.26 µM, 4.708 µM of IC50, respectively. Further study shows that the N-phenyl pyrazoline 5 suppresses the cell proliferation and migration ability of HeLa cell line in a dose-dependent manner. Target prediction and molecular docking reveal that EGFR and ERBB2 protein as the main target of the N-phenyl pyrazoline 5 compound. The N-phenyl pyrazoline 5 suppresses the EGFR expression level but not the total ERK1/2. Public data and GSEA analysis found that the EGFR high expression level is positively associated with poor survival, cancer metastasis-related signaling pathways, and cancer stem cell markers in cervical cancer patients. In addition, the N-phenyl pyrazoline 5 reduces the HeLa's tumorsphere size and cancer stem cell marker, CD133.
Conclusion: N-phenyl pyrazoline 5 suppresses the cell viability, proliferation, migration, and cancer stem cell-like phenotype of cervical cancer cells via EGFR inhibition.

Keywords:  EGFR; N-phenyl pyrazoline; cancer stem cell-like phenotype; cervical cancer

DOI:  https://doi.org/10.2147/DDDT.S350913
Int J Oncol. 2022 Sep;pii: 108. [Epub ahead of print]61(3):

Cryptotanshinone suppresses tumorigenesis by inhibiting lipogenesis and promoting reactive oxygen species production in KRAS‑activated pancreatic cancer cells.

Tokio Terado, Chul Jang Kim, Akiyo Ushio, Kahori Minami, Yukihiro Tambe, Susumu Kageyama, Akihiro Kawauchi, Toshiyuki Tsunoda, Senji Shirasawa, Hiroyuki Tanaka, Hirokazu Inoue.

  Pyruvate dehydrogenase kinase 4 (PDK4) is an important regulator of energy metabolism. Previously, knockdown of PDK4 by specific small interfering RNAs (siRNAs) have been shown to suppress the expression of Κirsten rat sarcoma viral oncogene homolog (KRAS) and the growth of lung and colorectal cancer cells, indicating that PDK4 is an attractive target of cancer therapy by altering energy metabolism. The authors previously reported that a novel small molecule, cryptotanshinone (CPT), which inhibits PDK4 activity, suppresses the in vitro three‑dimensional (3D)‑spheroid formation and in vivo tumorigenesis of KRAS‑activated human pancreatic and colorectal cancer cells. The present study investigated the molecular mechanism of CPT‑induced tumor suppression via alteration of glutamine and lipid metabolism in human pancreatic and colon cancer cell lines with mutant and wild‑type KRAS. The antitumor effect of CPT was more pronounced in the cancer cells containing mutant KRAS compared with those containing wild‑type KRAS. CPT treatment decreased glutamine and lipid metabolism, affected redox regulation and increased reactive oxygen species (ROS) production in the pancreatic cancer cell line MIAPaCa‑2 containing mutant KRAS. Suppression of activated KRAS by specific siRNAs decreased 3D‑spheroid formation, the expression of acetyl‑CoA carboxylase 1 and fatty acid synthase (FASN) and lipid synthesis. The suppression also reduced glutathione‑SH/glutathione disulfide and increased the production of ROS. Knockdown of FASN suppressed lipid synthesis in MIAPaCa‑2 cells, partially promoted ROS production and mildly suppressed 3D‑spheroid formation. These results indicated that CPT reduced tumorigenesis by inhibiting lipid metabolism and promoting ROS production in a mutant KRAS‑dependent manner. This PDK4 inhibitor could serve as a novel therapeutic drug for KRAS‑driven intractable cancers via alteration of cell metabolism.

Keywords:  KRAS; PDK4 inhibitor; acetyl‑CoA carboxylase 1; cryptotanshinone; fatty acid synthase; lipid synthesis; pancreatic neoplasm; reactive oxygen species

DOI:  https://doi.org/10.3892/ijo.2022.5398