Polypeptide LTX‐315 reverses the cisplatin chemoresistance of ovarian cancer cells via regulating Beclin‐1/PI3K/mTOR signaling pathway

Abstract

Objective: Polypeptide LTX-315 induces immunogenic cell death, thus having the potential to improve the effect of anticancer treatment. However, the function of LTX-315 in reversing chemoresistance in ovarian cancer (OC) still remains elusive.Our study aims to decipher the effect of LTX-315 on reversing the chemoresistance of OC cells and explore its mechanism. Methods: SKOV3, A2780, SKOV3/DDP, and A2780/DDP cells (cisplatin [DDP]resistant cells] were treated with different concentrations of LTX-315 (10 and 20 µmol/L), respectively. Cell counting kit-8 assay, Transwell assay, and flow cytometry were used to assess cell viability, migration, invasion, apoptosis rate, and cell cycle of the cells. Western blot was performed to examine the expression of cleaved caspase 3, caspase 3, cleaved Poly (ADP-ribose) polymerase (PARP), PARP, Bax, Bcl-2, Beclin-1, p-Akt, Akt, p-mammalian target of rapamycin (mTOR), and mTOR. Furthermore, OC cells were treated with autophagy inhibitor 3-methyladenine (3-MA), and "rescue experiments" were performed. Results: DDP-resistant OC cell models were established, and LTX-315 treatment resulted in lower IC 50 of DDP. In OC cells treated with LTX-315, the viability, migration, invasion and the expression of Bcl-2 of were repressed, but the apoptotic rate and the expression of cleaved caspase 3, cleaved PARP and Bax were increased, and the cell cycle was arrested. Moreover, LTX-315 promoted Beclin-1 expression level and inhibited p-Akt and p-mTOR expression levels, whereas 3-MA could partially reverse the biological effects of LTX-315 on OC cells. Conclusion: LTX-315 can inhibit the resistance of OC cells to DDP in vitro and plays a role by regulating Beclin-1/phosphatidylinositol-3-kinase/mTOR signaling pathway.

Role of autophagy and its regulation by noncoding RNAs in ovarian cancer

“…24 Beclin-1 is indispensable to initiate the autophagy process, and reduced level of autophagy in OC is consistent with decreased expression of Beclin-1. 25 Several previous studies showed that the expression of Beclin-1 was higher in ovarian epithelial cancer and borderline tumor than that in benign ovarian tumors and normal ovarian tissue, and that higher levels of Beclin-1 were inversely related to the differentiation, FIGO stage, and histological grade of OC. [26][27][28] In addition, the low expression of Beclin-1 in aggressive OC is correlated with ascending histological grade, later TNM staging, and advanced clinical stage.…”

“…43 Furthermore, several anticancer agents, such as LTX-315 and tanshinone I, mediate OC cell apoptosis and the cisplatin chemosensitivity by inducing autophagy through the inactivation of the PI3K/AKT/mTOR pathway. 25,44…”