MicroRNA-199a-5p inhibits cisplatin-induced drug resistance via inhibition of autophagy in osteosarcoma cells

Abstract

Abstract. Osteosarcoma (OS) is the most common cancer of the bone. Chemotherapy is commonly used for the clinical treatment of OS. However, chemoresistance to cisplatin [also known as diamminedichloridoplatinum (II) (DDP)] is a major obstacle for OS therapy, the underlying mechanism of which is not fully understood. The present study aimed to investigate the role of microRNA (miR)-199a-5p in the regulation of chemoresistance to DDP in OS cells. Reverse transcription-quantitative polymerase chain reaction demonstrated that the expression level of miR-199a-5p was significantly reduced in human OS MG63 cells. In addition, DDP treatment also upregulated the protein levels of light chain 3 (LC3)-II and Beclin1 as well as the ratio of LC3-II vs. LC3-I in MG63 cells, indicating that autophagy was activated. Restoration of miR-199a-5p expression promoted DDP-induced inhibition of MG63 cell proliferation and inhibited DDP-induced autophagy, as indicated by the reduced protein levels of LC3-II and Beclin1 and the ratio of LC3-II vs. LC3-I. Finally, luciferase reporter assay data revealed that miR-199a-5p directly targeted Beclin1 and negatively mediated Beclin1 expression at a post-transcriptional level in MG63 cells. In conclusion, our study suggests that miR-199a-5p promotes the cytotoxicity of DDP in OS cells via inhibition of autophagy. Therefore, miR-199a-5p/autophagy signaling is involved in chemoresistance and may become a potential target for the treatment of DDP-resistant OS.

CircMUC16 promotes autophagy of epithelial ovarian cancer via interaction with ATG13 and miR-199a

“…miR-199a suppressed autophagy by GSK3β/mTOR complex signaling [22]. Moreover, miR-199a directly targeted Beclin1 to inhibited autophagy and reversed drug resistance induced by cisplatin of osteosarcoma cells [23]. Our results also demonstrated that miR-199a targetly regulated Beclin1, which was consistent with the previous study.…”

Downregulation of BAG3 attenuates cisplatin resistance by inhibiting autophagy in human epithelial ovarian cancer cells

“…Cisplatin induced autophagy in a concentration-dependent manner in the examined cells, as demonstrated by the western blot results for the autophagy markers LC3-I, LC3-II and p62. This compound has previously been demonstrated to induce autophagy in various types of cancer cells, such as ovarian cancer cells and osteosarcoma cancer cells (35,36), and another study indicated that autophagy serves a protective role in cisplatin resistance (34). The results of the present study demonstrated that the blockade of autophagy promoted cisplatin-induced cell death in SKOV3 and SKOV3/DDP cells, and partially re-sensitized cisplatin-resistant SKOV3/DDP cells.…”

Novel strategies to prevent the development of multidrug resistance (MDR) in cancer

“…Intrinsic or acquired MDR is one of the main reasons for chemotherapy failure, leading to the recurrence of malignant tumors and ultimately, patient relapse or death [ 3 ]. Various mechanisms have been attributed to MDR, such as enhanced drug efflux, increased DNA damage repair, reduced apoptosis, elevated autophagy, and/or altered drug metabolism [ 2 , 4 – 6 ]. In order to improve the efficacy of chemotherapy, strategies to reverse MDR have been studied extensively over the past few decades.…”