Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Zhang Q

PROVIDER: S-EPMC3879005 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Publications

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

Zhang Qi Q Si Shuhui S Schoen Sue S Chen Jindong J Jin Xun-Bo XB Wu Guan G

Journal of experimental & clinical cancer research : CR 20131204

<h4>Background</h4>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.<h4>Methods</h4>Two pairs of cell lines were used: FLCN siRNA-silenced ACHN cell line (ACHN-5968) an ...[more]

PMID: 24305604

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Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

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