Jian‐Hua Zheng

LDLR promotes autophagy‐mediated cisplatin resistance in ovarian cancer associated with the PI3K/AKT/mTOR signaling pathway

AbstractAutophagy is one of the underlying causes of resistance to many antitumor drugs, including cisplatin (DDP). The low‐density lipoprotein receptor (LDLR) is a regulator of ovarian cancer (OC) progression. However, whether LDLR regulates DDP resistance in OC via autophagy‐related pathways remains unclear. LDLR expression was measured by quantitative real‐time PCR, western blot (WB) and IHC staining. A Cell Counting Kit 8 assay was employed to evaluate DDP resistance and cell viability, and flow cytometry was used to assess apoptosis. WB analysis was employed to evaluate the expression of autophagy‐related proteins and PI3K/AKT/mTOR signaling pathway proteins. The autophagolysosomes and the fluorescence intensity of LC3 were observed by transmission electron microscopy and immunofluorescence staining, respectively. A xenograft tumor model was established to explore the role of LDLR in vivo. LDLR was highly expressed in OC cells, which was correlated with disease progression. In DDP‐resistant OC cells, high LDLR expression was related to DDP resistance and autophagy. Downregulation of LDLR repressed autophagy and growth in DDP‐resistant OC cell lines by activating the PI3K/AKT/mTOR pathway, and these effects were eliminated by an mTOR inhibitor. In addition, LDLR knockdown also reduced OC tumor growth by suppressing autophagy associated with the PI3K/AKT/mTOR pathway. LDLR promoted autophagy‐mediated DDP resistance in OC associated with the PI3K/AKT/mTOR pathway, indicating that LDLR might be a new target to prevent DDP resistance in OC patients.

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

AbstractObjectivePolypeptide 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.MethodsSKOV3, 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.ResultsDDP‐resistant OC cell models were established, and LTX‐315 treatment resulted in lower IC50 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.ConclusionLTX‐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.