Knockdown of CFTR enhances sensitivity of prostate cancer cells to cisplatin via inhibition of autophagy

Abstract

Prostate cancer is one of the most lethal diseases in men worldwide. Although the survival rate of men diagnosed with prostate cancer has increased with the improvement of treatments, drug resistance still remains a big challenge for improving overall survival. Cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated anion channel, has been reported to have a pivotal role in the pathogenesis of various cancers, but its role in chemoresistance of prostate cancer cells is poorly understood. In our study, we found that CFTR expression was significantly increased in prostate cancer tissues associated the chemoresistance, and in the cisplatin-resistant cell line LNCaP/CP compared with their respective parental cells. Cisplatin treatment inhibited CFTR expression in a concentration-dependent manner, which was correlated with a decrease in cell viability. Moreover, inhibition of CFTR by transfection of small interfering RNA enhanced cisplatin-induced the decrease of cell viability. Autophagy was dramatically increased in LNCaP/CP cells, as evidenced by autopaphgic markers as well as fluorescence microscopy analysis of GFP-LC3, MDC and AO staining. Of note, inhibiting autophagy by 3MA induced LNCaP/CP cell apoptosis, showed by MTT assay and Hoechst 33258 staining. In addition, blockade of CFTR also inhibited LNCaP/CP cell viability and autophagy. Furthermore, the dephosphorylation of AKT and mTOR was reversed by CFTR inhibition, indicating the knockdown of CFTR might inhibit autophagy in LNCaP/CP cells via activation of AKT/mTOR signaling. Altogether, these results provide a novel understanding of the mechanism for acquired cisplatin. Inhibition of CFTR may be a useful strategy to increase the efficacy of cisplatin to treat prostate cancer by preventing the protective response of autophagy.

Homocysteine activates autophagy by inhibition of CFTR expression via interaction between DNA methylation and H3K27me3 in mouse liver

“…Loss of functional CFTR expression is thought to disturb the balance between fluid secretion and absorption into the epithelial layer, leading to cystic fibrosis liver disease 9 , 10 . Accordingly, a depressed autophagy has previously been reported in prostate cancer cells due to knockdown of CFTR 11 , 12 . Notably, liver is a major metabolic organ of Hcy, but there is no evidence to show the correlation between CFTR and hepatic autophagy induced by Hcy.…”

Inhibition of autophagy enhances synergistic effects of Salidroside and anti-tumor agents against colorectal cancer

“…That is because some plant extracts trigger the generation of autophagy of cancer cells while suppressing the proliferation [ 7 , 9 ]. Autophagy confers protective effect against toxicity of anti-tumor agents, thus it, to some extent, inhibits apoptosis of cancerous cells and results in chemo-resistance [ 17 ]. Sal has been emerged as an important plant extracts for the treatments of cancer and age-related diseases [ 18 ].…”

CFTR improves myocardial ischemic/reperfusion injury through activating FUNDC1-mediated mitophagy and regulating ATP and mitochondrial functions

“…The activation effect of CFTR on autophagy was also found in prostate cancer. (18) However, relationship between CFTR and mitophagy is rarely reported. Here, we observed CFTR could also activate mitophagy in cardiomyocytes, and de ciency of CFTR might result in worse I/R injury.…”

“…In recent years, role of CFTR in other diseases are also reported. It was found inhibition of CFTR might promote prostate cancer sensitivity to cisplatin by inhibition of autophagy (18). Another study also showed CFTR could inhibit epidermal growth factor receptor-dependent proin ammatory chemokine production (19).…”