IL-6 promotes drug resistance through formation of polyploid giant cancer cells and stromal fibroblast reprogramming

AbstractTo understand the role of polyploid giant cancer cells (PGCCs) in drug resistance and disease relapse, we examined the mRNA expression profile of PGCCs following treatment with paclitaxel in ovarian cancer cells. An acute activation of IL-6 dominated senescence-associated secretory phenotype lasted 2–3 weeks and declined during the termination phase of polyploidy. IL-6 activates embryonic stemness during the initiation of PGCCs and can reprogram normal fibroblasts into cancer-associated fibroblasts (CAFs) via increased collagen synthesis, activation of VEGF expression, and enrichment of CAFs and the GPR77 + /CD10 + fibroblast subpopulation. Blocking the IL-6 feedback loop with tocilizumab or apigenin prevented PGCC formation, attenuated embryonic stemness and the CAF phenotype, and inhibited tumor growth in a patient-derived xenograft high-grade serous ovarian carcinoma model. Thus, IL-6 derived by PGCCs is capable of reprogramming both cancer and stromal cells and contributes to the evolution and remodeling of cancer. Targeting IL-6 in PGCCs may represent a novel approach to combating drug resistance.

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PAI-1 secreted from metastatic ovarian cancer cells triggers the tumor-promoting role of the mesothelium in a feedback loop to accelerate peritoneal dissemination

Cancer Letters ◽

10.1016/j.canlet.2018.10.027 ◽

2019 ◽

Vol 442 ◽

pp. 181-192 ◽

Cited By ~ 9

Author(s):

Yang Peng ◽

Hiroaki Kajiyama ◽

Hong Yuan ◽

Kae Nakamura ◽

Masato Yoshihara ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Feedback Loop ◽

Peritoneal Dissemination ◽

Ovarian Cancer Cells ◽

Pai 1

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Inhibition of Tyrosine 3-Monooxygenase/Tryptophan 5-Monooxygenase Activation Protein Zeta (YWHAZ) Overcomes Drug Resistance and Tumorigenicity in Ovarian Cancer

Cellular Physiology and Biochemistry ◽

10.1159/000492839 ◽

2018 ◽

Vol 49 (1) ◽

pp. 53-64 ◽

Cited By ~ 6

Author(s):

Lan Hong ◽

Wangsheng Chen ◽

Aiwen Xing ◽

Dongcai Wu ◽

Shengtan Wang

Keyword(s):

Cell Cycle ◽

Ovarian Cancer ◽

Drug Resistance ◽

Stem Cell ◽

Cancer Cells ◽

Functional Role ◽

Ovarian Cancer Cells ◽

Stem Cell Markers ◽

Western Blots

Background/Aims: Cancer stem-like cells are the main cause of tumor occurrence, progression, and therapeutic resistance. However, the precise signals required for the maintenance of the stem-like traits of these cells in ovarian cancer remain elusive. We have thus worked to elucidate the functional role of Tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ), a gene encoding the 14-3-3ζ protein, in the regulation of multidrug resistance and stem cell-like traits in ovarian cancer. Methods: We detected the YWHAZ levels in human ovarian cancer specimens and cell lines using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blots. MTS assays, soft agar colony formation assays, migration assays, cell cycle analysis, sphere formation assays, and flow cytometry were applied to investigate the functional role of YWHAZ in ovarian cancer. Results: Our data reveals substantially increased YWHAZ expression in both cisplatin- and paclitaxel-resistant ovarian cancer cells. Silencing YWHAZ restored the sensitivity of resistant ovarian cancer cells to cisplatin and paclitaxel. Furthermore, in vitro studies showed that down-regulation of YWHAZ inhibited cell cycle progression, migration, and the expression of stem cell markers. Moreover, tumorigenicity was suppressed in tumor-bearing BALB/c nude mice following YWHAZ knockdown. Additionally, we demonstrated that the expression of YWHAZ was directly down-regulated by miR-30e in resistant ovarian cancer cells. Conclusion: Our results have led to new insights into the essential role of YWHAZ in the regulation of tumourigenesis, stem-like traits, and drug resistance in ovarian cancer, thereby helping to identify a potential target for ovarian cancer therapy.

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A Novel Approach to Identify Genes that Modulate Response of Human Ovarian Cancer Cells to Chemotherapeutic Agents Using High-Throughput RNA Interference

10.21236/ada510407 ◽

2008 ◽

Author(s):

David Azorsa

Keyword(s):

Ovarian Cancer ◽

Rna Interference ◽

Cancer Cells ◽

High Throughput ◽

Chemotherapeutic Agents ◽

Ovarian Cancer Cells ◽

Human Ovarian Cancer ◽

Novel Approach

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Emodin Enhances the Chemosensitivity of Endometrial Cancer by Inhibiting ROS-Mediated Cisplatin-resistance

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520618666171219113036 ◽

2018 ◽

Vol 18 (7) ◽

pp. 1054-1063 ◽

Cited By ~ 4

Author(s):

Ning Ding ◽

Hong Zhang ◽

Shan Su ◽

Yumei Ding ◽

Xiaohui Yu ◽

...

Keyword(s):

Drug Resistance ◽

Endometrial Cancer ◽

Cancer Cells ◽

Chemotherapeutic Agent ◽

Annexin V ◽

Chemotherapeutic Agents ◽

Endometrial Cancer Cell ◽

Animal Survival ◽

Apoptosis Level

Background: Endometrial cancer is a common cause of death in gynecological malignancies. Cisplatin is a clinically chemotherapeutic agent. However, drug-resistance is the primary cause of treatment failure. Objective: Emodin is commonly used clinically to increase the sensitivity of chemotherapeutic agents, yet whether Emodin promotes the role of Cisplatin in the treatment of endometrial cancer has not been studied. Method: CCK-8 kit was utilized to determine the growth of two endometrial cancer cell lines, Ishikawa and HEC-IB. The apoptosis level of Ishikawa and HEC-IB cells was detected by Annexin V / propidium iodide double-staining assay. ROS level was detected by DCFH-DA and NADPH oxidase expression. Expressions of drug-resistant genes were examined by real-time PCR and Western blotting. Results: Emodin combined with Cisplatin reduced cell growth and increased the apoptosis of endometrial cancer cells. Co-treatment of Emodin and Cisplatin increased chemosensitivity by inhibiting the expression of drugresistant genes through reducing the ROS levels in endometrial cancer cells. In an endometrial cancer xenograft murine model, the tumor size was reduced and animal survival time was increased by co-treatment of Emodin and Cisplatin. Conclusion: This study demonstrates that Emodin enhances the chemosensitivity of Cisplatin on endometrial cancer by inhibiting ROS-mediated expression of drug-resistance genes.

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Multifunctional Role of Astrocyte Elevated Gene-1 (AEG-1) in Cancer: Focus on Drug Resistance

Cancers ◽

10.3390/cancers13081792 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1792

Author(s):

Debashri Manna ◽

Devanand Sarkar

Keyword(s):

Drug Resistance ◽

Cancer Cells ◽

Cancer Development ◽

Epigenetic Alterations ◽

Hallmarks Of Cancer ◽

Comprehensive Description ◽

Molecular Abnormalities ◽

Selective Pressures ◽

Resistance To Chemotherapy

Cancer development results from the acquisition of numerous genetic and epigenetic alterations in cancer cells themselves, as well as continuous changes in their microenvironment. The plasticity of cancer cells allows them to continuously adapt to selective pressures brought forth by exogenous environmental stresses, the internal milieu of the tumor and cancer treatment itself. Resistance to treatment, either inherent or acquired after the commencement of treatment, is a major obstacle an oncologist confronts in an endeavor to efficiently manage the disease. Resistance to chemotherapy, chemoresistance, is an important hallmark of aggressive cancers, and driver oncogene-induced signaling pathways and molecular abnormalities create the platform for chemoresistance. The oncogene Astrocyte elevated gene-1/Metadherin (AEG-1/MTDH) is overexpressed in a diverse array of cancers, and its overexpression promotes all the hallmarks of cancer, such as proliferation, invasion, metastasis, angiogenesis and chemoresistance. The present review provides a comprehensive description of the molecular mechanism by which AEG-1 promotes tumorigenesis, with a special emphasis on its ability to regulate chemoresistance.

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Plasma cells shape the mesenchymal identity of ovarian cancers through transfer of exosome-derived microRNAs

Science Advances ◽

10.1126/sciadv.abb0737 ◽

2021 ◽

Vol 7 (9) ◽

pp. eabb0737

Author(s):

Zhengnan Yang ◽

Wei Wang ◽

Linjie Zhao ◽

Xin Wang ◽

Ryan C. Gimple ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Plasma Cell ◽

Plasma Cells ◽

Ovarian Cancer Cells ◽

Mesenchymal Phenotype ◽

Ovarian Cancers ◽

Novel Approach

Ovarian cancer represents a highly lethal disease that poses a substantial burden for females, with four main molecular subtypes carrying distinct clinical outcomes. Here, we demonstrated that plasma cells, a subset of antibody-producing B cells, were enriched in the mesenchymal subtype of high-grade serous ovarian cancers (HGSCs). Plasma cell abundance correlated with the density of mesenchymal cells in clinical specimens of HGSCs. Coculture of nonmesenchymal ovarian cancer cells and plasma cells induced a mesenchymal phenotype of tumor cells in vitro and in vivo. Phenotypic switch was mediated by the transfer of plasma cell–derived exosomes containing miR-330-3p into nonmesenchymal ovarian cancer cells. Exosome-derived miR-330-3p increased expression of junctional adhesion molecule B in a noncanonical fashion. Depletion of plasma cells by bortezomib reversed the mesenchymal characteristics of ovarian cancer and inhibited in vivo tumor growth. Collectively, our work suggests targeting plasma cells may be a novel approach for ovarian cancer therapy.

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The role of Sox6 and Netrin-1 in ovarian cancer cell growth, invasiveness, and angiogenesis

Tumor Biology ◽

10.1177/1010428317705508 ◽

2017 ◽

Vol 39 (5) ◽

pp. 101042831770550 ◽

Cited By ~ 4

Author(s):

Yi Li ◽

Ming Xiao ◽

Fangchun Guo

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Conditioned Medium ◽

Umbilical Vein ◽

Inhibitory Effect ◽

Ovarian Cancer Cells ◽

Human Umbilical Vein ◽

Tumor Tissues

SOX6 plays important roles in cell proliferation, differentiation, and cell fate determination. It has been confirmed that SOX6 is a tumor suppressor and downregulated in various cancers, including esophageal squamous cell carcinoma, hepatocellular carcinoma, and chronic myeloid leukemia. Netrin-1 is highly expressed in various human cancers and acts as an anti-apoptotic and proangiogenic factor to drive tumorigenesis. The role of SOX6 and netrin-1 in regulating the growth of ovarian tumor cells still remains unclear. Real-time polymerase chain reaction and western blot were used to determine the SOX6 messenger RNA and protein levels, respectively, in ovarian cancer cells and tumor tissues. Stable transfection of SOX6 was conducted to overexpress SOX6 in PA-1 and SW626 cells. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Invasion of ovarian cancer cells and migration of human umbilical vein endothelial cells were confirmed by Transwell assays. To overexpress netrin-1, ovarian cancer cells with SOX6 restoration was transduced with netrin-1 lentiviral particles. PA-1 xenografts in a nude mice model were used to conduct in vivo evaluation of the role of SOX6 and its relationship with netrin-1 in tumor growth and angiogenesis. In this study, we found significantly reduced SOX6 levels in PA-1, SW626, SK-OV-3, and CaoV-3 ovarian cancer cell lines and human tumor tissues in comparison with normal human ovarian epithelial cells or matched non-tumor tissues. SOX6 overexpression by stable transfection dramatically inhibited proliferation and invasion of PA-1 and SW626 cells. Also, conditioned medium from PA-1 and SW626 cells with SOX6 restoration exhibited reduced ability to induce human umbilical vein endothelial cells migration and tube formation compared with conditioned medium from the cells with transfection control. Furthermore, an inverse relationship between SOX6 and netrin-1 expression was observed in PA-1 and SW626 cells. Overexpression of netrin-1 in ovarian cancer cells with forced SOX6 expression remarkably abrogated the inhibitory effect of SOX6 on proliferation, invasion of the cells, and tumor xenograft growth and vascularity in vivo. Human umbilical vein endothelial cell migration and tube formation were enhanced in the conditioned medium from the ovarian cancer cells transduced with netrin-1 lentivirus particles. Our observations revealed that SOX6 is a tumor suppressor in ovarian cancer cells, and SOX6 exerts an inhibitory effect on the proliferation, invasion, and tumor cell-induced angiogenesis of ovarian cancer cells, whereas nerin-1 plays an opposite role and its expression is inversely correlated with SOX6. Moreover, our findings suggest a new role of SOX6 and netrin-1 for understanding the progression of ovarian cancer and have the potential for the development of new diagnosis and treatment strategies for ovarian cancer.

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