Suppression of autophagy enhances preferential toxicity of paclitaxel to folliculin-deficient renal cancer cells

Background: paclitaxel,a widely used chemotherapeutic drug,can induce apoptosis in variety of cancer cells. a previous study has shown preferential toxicity of paclitaxel to flcn-deficient kidney cancer cell line,uok257. in this report,we investigate the cellular and molecular mechanism of paclitaxel-induced autophagy and apoptosis in renal cancer cells with and without flcn expression. methods. two pairs of cell lines were used: flcn sirna-silenced achn cell line (achn-5968) and scrambled achn cell line (achn-sc); flcn-null uok257 cell line and uok257-2 cell line restored with ectopic expression of flcn. autophagy was examined by western blot,gfp-lc3,transmission electron microscopy,and mdc assay. cell viability and apoptosis were detected using mtt assay,dapi stain and tunel assay. after inhibition of autophagy with 3-methyladenine (3-ma) or beclin 1 sirna,cell viability and apoptosis were measured by mtt assay and tunel assay. results: after paclitaxel treatment,a dose-dependent decrease in cell viability and increase in apoptosis were observed in flcn-deficient uok257 and achn-5968 cells compared to their flcn-expressing counterparts,suggesting that renal cancer cells without flcn were more sensitive to paclitaxel. enhanced autophagy was found to be associated with paclitaxel treatment in flcn-deficient rcc cells. the mapk pathway was also identified as a key pathway for the activation of autophagy in these kidney cancer cells. inhibition of phosphorylated erk with erk inhibitor u0126 showed a significant decrease in autophagy. furthermore,after inhibition of autophagy with 3-methyladenine (3-ma) or beclin 1 sirna,apoptosis induced by paclitaxel was significantly increased in flcn-deficient uok257 and achn-5968 cells. conclusions: preferential toxicity of paclitaxel to flcn-deficient kidney cancer cells is associated with enhanced autophagy. suppression of autophagy further enhances paclitaxel-induced apoptosis in flcn-deficient renal cancer cells. our results suggest that paclitaxel combined with an autophagy inhibitor might be a potentially more effective chemotherapeutic approach for flcn-deficient renal cancer. © 2013 zhang et al.; licensee biomed central ltd.