Twist2 contributes to cisplatin-resistance of ovarian cancer through the AKT/GSK-3β signaling pathway

Abstract Background Chemotherapy resistance remains a barrier to improving the prognosis of epithelial ovarian cancer (EOC). ALKBH5 has recently been shown to be one of the RNA N6-methyladenosine (m6A) demethyltransferases associated with various cancers, but its role in cancer therapeutic resistance remains unclear. This study aimed to investigate the role of AlkB homolog 5 (ALKBH5) in cisplatin-resistant EOC. Methods Functional assays were performed both in vitro and in vivo. RNA sequencing (RNA-seq), m6A-modified RNA immunoprecipitation sequencing (MeRIP-seq), chromatin immunoprecipitation, RNA immunoprecipitation, and luciferase reporter and actinomycin-D assays were performed to investigate RNA/RNA interaction and m6A modification of the ALKBH5-HOXA10 loop. Results ALKBH5 was upregulated in cisplatin-resistant EOC and promoted cancer cell cisplatin resistance both in vivo and in vitro. Notably, HOXA10 formed a loop with ALKBH5 and was found to be the upstream transcription factor of ALKBH5. HOXA10 overexpression also facilitated EOC cell chemoresistance both in vivo and in vitro. Collective results of MeRIP-seq and RNA-seq showed that JAK2 is the m6A-modified gene targeted by ALKBH5. The JAK2/STAT3 signaling pathway was activated by overexpression of the ALKBH5-HOXA10 loop, resulting in EOC chemoresistance. Cell sensitivity to cisplatin was rescued by ALKBH5 and HOXA10 knockdown or inhibition of the JAK2/STAT3 signaling pathway in EOC cells overexpressing ALKBH5-HOXA10. Conclusions The ALKBH5-HOXA10 loop jointly activates the JAK2/STAT3 signaling pathway by mediating JAK2 m6A demethylation, promoting EOC resistance to cisplatin. Thus, inhibition of the expression of the ALKBH5-HOXA10 loop may be a potential strategy to overcome cisplatin resistance in EOC.

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Reversal of cisplatin resistance by microRNA-139-5p-independent RNF2 downregulation and MAPK inhibition in ovarian cancer

AJP Cell Physiology ◽

10.1152/ajpcell.00283.2017 ◽

2018 ◽

Vol 315 (2) ◽

pp. C225-C235 ◽

Cited By ~ 14

Author(s):

Ying Chen ◽

Xiao-Yun Cao ◽

Ying-Ni Li ◽

Yu-Yan Qiu ◽

Ying-Na Li ◽

...

Keyword(s):

Ovarian Cancer ◽

Signaling Pathway ◽

Cisplatin Resistance ◽

Quantitative Polymerase Chain Reaction ◽

Ring Finger ◽

Annexin V ◽

Mapk Signaling ◽

Mapk Signaling Pathway ◽

Mitogen Activated Protein Kinase ◽

Cell Vitality

Some microRNAs (miRs) are dysregulated in cancers, and aberrant miR expression has been reported to correlate with chemoresistance of cancer cells. Therefore, the present study aims at investigating the effects of microRNA-139-5p (miR-139-5p) on cisplatin resistance of ovarian cancer (OC) with involvement of ring finger protein 2 (RNF2) and the mitogen-activated protein kinase (MAPK) signaling pathway. OC tissues were obtained from 66 primary OC patients. The cisplatin-sensitive A2780 and cisplatin-resistant A2780/DDP cell lines were collected for construction of RNF2 silencing and overexpressed plasmids. Cell vitality and apoptosis were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and annexin V-FITC/propidium iodide double-staining, respectively. Next, expression of RNF2, extracellular signal-related kinase, and p38 was determined by quantitative reverse transcription-quantitative polymerase chain reaction and Western blot analysis. Finally, the volume of xenograft tumors in BALB/c nude mice was detected. RNF2 and miR-139-5p were identified to be involved in OC. In addition, MAPK activation and RNF2 were related to cisplatin resistance of OC. miR-139-5p was downregulated in cisplatin-resistant OC tissues, and miR-139-5p overexpression could inhibit cell vitality, reduce cisplatin resistance, and promote apoptosis of OC cells. Furthermore, miR-139-5p combined with MAPK inhibitors more obviously reduced cisplatin resistance of OC. Taken together, this study demonstrated that miR-139-5p overexpression combined with inactivation of the MAPK signaling pathway can reverse the cisplatin resistance of OC by suppressing RNF2. Thus, miR-139-5p overexpression might be a future therapeutic strategy for OC.

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Implication of BAG5 Downregulation in Metabolic Reprogramming of Cisplatin-resistant Ovarian Cancer Cells via mTORC2 Signaling Pathway

10.21203/rs.3.rs-97870/v1 ◽

2020 ◽

Author(s):

Jia-Mei Wang ◽

Qi Zhang ◽

Liang Hao ◽

Jing-Yi Jiang ◽

Ling-Yue Huyan ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Signaling Pathway ◽

Cisplatin Resistance ◽

Metabolic Reprogramming ◽

Migration And Invasion ◽

Ovarian Cancer Cells ◽

Serous Adenocarcinoma ◽

Metabolism Regulation ◽

Ovarian Serous Adenocarcinoma

Abstract Background: Ovarian cancer is the most frequent cause of death among gynecologic malignancies due to the absence of an early effective diagnostic approach. Although the majority of patients typically respond well to the first line of chemotherapy based on platinum compounds and taxanes, recurrence and chemoresistance limits its clinical utility. Remarkably, cancer stem cells (CSC) tend to form minimal residual disease after chemotherapy and exhibit recurrent potential. The ability of cancer cells to reprogram their metabolism has recently been related with resistance to chemotherapies.Methods: BAG5 expression was studied in 16 cisplatin-sensitive and 8 cisplatin-resistant ovarian cancer tissues by Western blot. BAG5-induced cell proliferation, migration and invasion were investigated by CCK-8 assay, colony formation assay, wound healing and Transwell assay. To investigate whether BAG5 is implicated in metabolism regulation, mitochondrial function was monitored by real-time measurement of changes in the oxygen consumption rate (OCR) and glycolysis was also determined by measuring the extracellular acidification rate (ECAR). Immunohistochemical staining measured correlations between BAG5 and Bcl6, Rictor in most ovarian serous adenocarcinoma tissues.Results: The current study found BAG5 expression was decreased in cisplatin-resistant ovarian cancer cells and clinical tissues. Our data demonstrated that BAG5 knockdown was implicated in metabolic reprogramming and maintenance of cancer stem cell (CSC)-like features of cisplatin-resistant ovarian cancer cells via regulation of Rictor and subsequent mTORC2 signaling pathway. In addition, the current study demonstrated that Bcl6 upregulation was responsible for repression of BAG5 transactivation via recruitment on the BAG5 promoter in cisplatin-resistant ovarian cancer. The current study also demonstrated reverse correlations between BAG5 and Bcl6, BAG5 and Rictor in ovarian serous adenocarcinoma tissues. Conclusions: Collectively, the current study identified the implication of Bcl6/BAG5/Rictor-mTORC2 signaling pathway in metabolic reprograming and maintenance of CSC-like features including cisplatin-resistance in cisplatin-resistant ovarian cancer cells. Therefore, further studies on the mechanism underlying regulation of metabolic reprogramming and CSC-like characteristics of cisplatin-resistant ovarian cancer cells may contribute to the establishment of novel therapeutic strategy for cisplatin-resistance.

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PGC1α Promotes Cisplatin Resistance in Ovarian Cancer by Regulating the HSP70/HK2/VDAC1 Signaling Pathway

International Journal of Molecular Sciences ◽

10.3390/ijms22052537 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2537

Author(s):

Yanqing Li ◽

Jinsong Kang ◽

Jiaying Fu ◽

Haoge Luo ◽

Yanan Liu ◽

...

Keyword(s):

Ovarian Cancer ◽

Signaling Pathway ◽

Protein Transport ◽

Cisplatin Resistance ◽

Anion Channel ◽

Underlying Mechanism ◽

Peroxisome Proliferator ◽

Voltage Dependent Anion Channel ◽

Peroxisome Proliferator Activated Receptor ◽

Resistant Cells

Mitochondrial apoptosis is one of the main mechanisms for cancer cells to overcome chemoresistance. Hexokinase 2 (HK2) can resist cancer cell apoptosis by expressing on mitochondria and binding to voltage-dependent anion channel 1 (VDAC1). We previously reported that peroxisome proliferator-activated receptor coactivator 1 α (PGC1α) is highly expressed in ovarian cancer cisplatin-resistant cells. However, the underlying mechanism remains unclear. Therefore, we evaluated the interaction between PGC1α and HK2 in ovarian cancer cisplatin-resistant cells. We found that the knockdown of PGC1α promotes the apoptosis of ovarian cancer cisplatin-resistant cells and increases their sensitivity to cisplatin. In addition, we found that the knockdown of PGC1α affects the mitochondrial membrane potential and the binding of HK2 and VDAC1. As the heat shock protein 70 (HSP70) family can help protein transport, we detected it and found that PGC1α can promote HSP70 gene transcription. Furthermore, HSP70 can promote an increase of HK2 expression on mitochondria and an increase of binding to VDAC1. Based on these results, PGC1α may reduce apoptosis through the HSP70/HK2/VDAC1 signaling pathway, thus promoting cisplatin resistance of ovarian cancer. These findings provide strong theoretical support for PGC1α as a potential therapeutic target of cisplatin resistance in ovarian cancer.

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