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.
Inhibition of the IGF signaling pathway reverses cisplatin resistance in ovarian cancer cells
