TRAP1 downregulation could overcome gefitinib resistance in NSCLC via EMT reversal

Abstract

The tumor necrosis factor receptor-associated protein 1 (TRAP1) is a mitochondrial heat shock protein that has been related to drug resistance in some tumors. Epithelial-mesenchymal transition (EMT) is known to play an important role in cancer progression, metastasis and drug resistance. The aim of the present study was to determine the role of TRAP1 on EMT in lung cancer cell lines and to evaluate the prognostic role of TRAP1 in NSCLC patients. We developed an in vitro model of acquired resistance to gefitinib by continuously treating HCC827 with escalating doses. The effects of TRAP1 on EMT and lung cancer migration and invasion in gefitinib resistance (GR) cells were examined by western blotting and confocal microscopy. Downregulation of TRAP1 through siRNA or G-TPP inhibited GR-induced EMT, as indicated by upregulation of E-cadherin, and downregulation of mesenchymal markers and transcriptional factors. TRAP1 expression was analysed by immunohistochemistry in a series of 97 NSCLC patients. TRAP1 expression correlates with poor outcome in NSCLC patients. We next showed that TRAP1 downregulation enhanced the reversal of TGF-β1-induced EMT and hypoxia-induced EMT. Furthermore, TRAP1 downregulation attenuated migration and invasion of HCC827GR cells. In conclusions, these results suggested that TRAP1 downregulation could overcome gefitinib resistance in NSCLC via EMT reversal in tumor microenvironment.