Autophagy as a potential therapeutic target during epithelial to mesenchymal transition in renal cell carcinoma: An in vitro study

Cancer progression toward invasive and metastatic disease is aided by reactivation of epithelial-mesenchymal transition (EMT), involving transdifferentiation of epithelial cells into mesenchymal phenotype. This leads to increased migratory and stem cell-like features in the cells. These EMT cells are more resistant to chemotherapy and it is hypothesized that the phenomenon of autophagy induces resistance, providing a survival strategy for cells.In the present study, we induced EMT-like phenotype in renal carcinoma cells and identified corresponding higher autophagy flux in these cells. The EMT transformed cells may be a representative of the resistant cancer stem cell(CSC)-like phenotype. Autophagy was identified as a potential mechanism of cell survival in these cells thus implying that autophagy inhibition can lead to enhanced cell death. We also observed that tumor cells especially EMT transformed cells, have been 'primed' to undergo autophagy by mTOR inhibition. We observed that combined use of autophagy inhibitor and temsirolimus (TEM) improved antitumor activity against RCC in EMT transformed metastatic cells. One of the approaches for inhibiting autophagy was the use of lysosomotropic anti-malarial drug, chloroquine (CQ) and we explored the therapeutic potential of combination of CQ and the mTOR inhibitor, TEM. EMT transformed cells showed increased cell cytotoxicity when autophagy was impaired by addition CQ with TEM. This led us to conclude that inhibition of autophagy with the current therapeutic regimen could be useful in targeting the EMT transformed cells along with the bulk tumor cells in RCC.