Abstract
BackgroundDocetaxel-based chemotherapy failure in advanced prostate carcinoma has partly been attributed to the resistance of prostate cancer (PC) cells to docetaxel-induced apoptosis. Hence, there is an urgent need to identify mechanisms of docetaxel chemoresistance and to develop new combination therapies.MethodsmiR-193a-5p level was evaluated by qPCR in prostate tissues and cell lines, and its expression in the tissues was also examined by in situ hybridization. PC cell line (PC3 cell) was transfected with miR-193a-5p mimic or its inhibitor, and then cell apoptosis and the expression of its downstream genes Bach2 and HO-1 were detected by TUNEL staining and Western blotting. Luciferase reporter assay was used to detect the effect of miR-193a-5p and Bach2 on HO-1 expression. Xenograft animal model was used to test the effect of miR-193a-5p and docetaxel on PC3 xenograft growth.ResultsmiR-193a-5p was upregulated in PC tissues and PC cell lines, with significant suppression of PC3 cell apoptosis induced by oxidative stress. Mechanistically, miR-193a-5p suppressed the expression of Bach2, a repressor of the HO-1 gene, by directly targeting the Bach2 mRNA 3′-UTR. Docetaxel treatment modestly decreased Bach2 expression and increased HO-1 level in PC3 cells, whereas a modest increase of HO-1 facilitated docetaxel-induced apoptosis. Notably, docetaxel-induced miR-193a-5p upregulation, which in turn inhibits Bach2 expression and thus relieves Bach2 repression of HO-1 expression, partly counteracted docetaxel-induced apoptosis, as evidenced by the increased Bcl-2 and decreased Bax expression. Accordingly, silencing of miR-193a-5p enhanced sensitization of PC3 cells to docetaxel-induced apoptosis. Finally, depletion of miR-193a-5p significantly reduced PC xenograft growth in vivo.ConclusionsSilencing of miR-193a-5p or blockade of the miR-193a-5p-Bach2-HO-1 pathway may be a novel therapeutic approach for castration-resistant PC.
Highlights
Docetaxel-based chemotherapy failure in advanced prostate carcinoma has partly been attributed to the resistance of prostate cancer (PC) cells to docetaxel-induced apoptosis
We examined miR-193a5p expression in the different PC cell lines (LNCap, PC3 and DU145) and bladder cancer cell lines (T24 and UM-UC-3) as well as in human normal prostate epithelial cell line (RWPE-1) and showed that miR-193a5p expression was significantly increased in three PC cell lines, but not bladder cancer cell lines compared with the normal prostate epithelial cell, with miR193a-5p level being about 1-fold up-regulated in three PC cell lines (Fig. 1c)
MiR-193a-5p upregulation suppresses PC3 cell apoptosis induced by H2O2 Because oxidative stress pathway is known to be the predominant pathway affected by miR-193a-3p in bladder cancer [17], we sought to determine the effect of miR193a-5p on oxidative stress-evoked cell proliferation and miR-193a-5p mediates docetaxel regulation of Heme oxygenase-1 (HO-1) expression and suppresses PC3 cell apoptosis by increasing HO-1 expression Because we found that miR-193a-5p inhibited PC3 cell apoptosis induced by oxidative stress, we investigated whether miR-193a-5p regulates the expression of oxidative stress-related genes, such as heme oxygenase-1 (HO-1) and NADPH oxidase subunits p47phox and p22phox
Summary
Docetaxel-based chemotherapy failure in advanced prostate carcinoma has partly been attributed to the resistance of prostate cancer (PC) cells to docetaxel-induced apoptosis. Recent studies showed that miR-193a-5p but only suppresses tumor growth, and promotes tumor progression through regulating cell proliferation [13, 14] and apoptosis, as well as through inducing drug resistance [15, 16]. A previous study reported that miR-193a-3p, another mature miRNA of miR-193a precursor family, regulates the multi-drug resistance of bladder cancer by targeting the LOXL4 gene [17]. It remains unclear whether miR-193a-5p is involved in the resistance of PC cells to docetaxel-induced apoptosis
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