miR-125b confers resistance of ovarian cancer cells to cisplatin by targeting pro-apoptotic Bcl-2 antagonist killer 1

Abstract

Chemotherapy is the preferred therapeutic approach for advanced ovarian cancer, but a successful long-term treatment is prevented by the development of drug resistance. Recent works have underlined the involvement of non-coding RNAs, microRNAs (miRNAs) in cancer development, with several conjectures regarding their possible involvement in the evolution of drug resistance. This study is to investigate the promoting effects and mechanism of miR-125b involved in the development of chemoresistance in ovarian cancer. The different expression of miR-125b in cisplatin-sensitive ovarian cancer cell line (OV2008) and its resistant variant (C13*) was identified by real-time PCR. An in vitro cytotoxicity assay and apoptosis assay using CCK-8 assay and flow cytometry, were carried out to detect the effect of miR-125b and Bak1 on cisplatin resistance of cells. Real-time PCR, Western blotting and luciferase reporter assay were used to detect whether Bak1 is a target of miR-125b. As compared with OV2008 cells, the expression levels of miR-125b in C13* cells were increased. It was found that the up-regulation of microRNA-125b caused a marked inhibition of cisplatin-induced cytotoxicity and apoptosis and a subsequent increase in the resistance to cisplatin in OV2008 and C13* cells. Moreover, Bak1 was a direct target of miR-125b, and down-regulation of Bak1 suppressed cisplatin-induced apoptosis and led to an increased resistance to cisplatin. Our study indicates that miR-125b has a significantly promoting effect on chemoresistance of C13* cells and up-regulation of miR-125b expression contributes to cisplatin resistance through suppression of Bak1 expression. This finding has important implications in the development of targeted therapeutics for overcoming cisplatin resistance in ovarian cancer.

NRF2-driven miR-125B1 and miR-29B1 transcriptional regulation controls a novel anti-apoptotic miRNA regulatory network for AML survival

“…33,34 Furthermore, NF-κB, JUN and C-MYC have been linked to increased NRF2 activity in human cancer (including AML) 10,35 and NRF2 has been shown to transcriptionally regulate miR-125B in kidney epithelia cells in response to cisplatin-induced toxicity. 36 Taken together, it is likely that NRF2 has a central role in the complex network regulating miR-29B and miR-125B in human AML.…”

microRNA-125b promotes leukemia cell resistance to daunorubicin by inhibiting apoptosis

“…miR-125b is downregulated in resistant Ehrlich ascites tumor cells (25) and has been shown to increase the apoptotic response to cisplatin treatment in breast cells (26). Conversely, miR-125b has been found to be upregulated in Taxol-resistant cancer (9), doxorubicin-resistant Ewing sarcoma (27), cisplatin-resistant ovarian cancer (28) and AML (18) cells. In the present study, miR-125b upregulation was found to increase cell survival compared with that in the control cells, whereas miR-125b downregulation was observed to decrease cell survival.…”

“…Previous studies have shown that members of the B-cell lymphoma (Bcl)-2 family and other factors involved in apoptosis are important targets of miR-125. Numerous proteins have been shown to affect apoptosis, including anti-apoptotic members of the Bcl-2 family, such as Bcl-w (30), Bcl-2 (31), myeloid cell leukemia sequence 1 (30,32) and Bcl-2-antagonist/killer (Bak)-1 (9,28,30,32), acting as the Bcl-2 homologous antagonist, and pro-apoptotic targets, including P53 (33), tumor protein p53-inducible nuclear protein 1 (TP53INP1) (34), tumor necrosis factor α-induced protein 3 (35) and p38α (36). High miR-125 expression has been shown to downregulate Bak-1 and TP53INP1, and consequently protects cells from apoptosis and promotes tumorigenesis (37).…”

Cytochalasin B inhibits the proliferation of human glioma U251 cells through cell cycle arrest and apoptosis

“…The negative control contained <0.1% dimethylsulfoxide without CB (0 mM). After 24, 48, 72, and 96 h, 10 mL CCK-8 reagent (CCK-8 assay kit for measuring cell proliferation and cytotoxicity; Beyotime Institute of Biotechnology, Haimen, China) was added to the cells and incubated for 2 h. Absorbance was measured at 450 nm as optical density (OD) values using a KHB ST-360 microplate reader (Kehua Laboratory System Co., Ltd., Shanghai, China) (Espindola et al, 2000;White et al, 2001;Kong et al, 2011). The percentages of cell viability were calculated in each group using the following formula: Cell viability (%) = (OD experimental -OD blank / OD control -OD blank ) x 100%.…”