Phosphorylation of Bcl‐2 by JNK confers gemcitabine resistance in lung cancer cells by reducing autophagy‐mediated cell death

Abstract

AbstractThe most common cancer‐related death in the world is non‐small cell lung cancer (NSCLC). Gemcitabine (GEM) is a common and effective first‐line chemotherapeutic drug for the treatment of NSCLC. However, the long‐term use of chemotherapeutic drugs in patients usually induces cancer cell drug resistance, leading to poor survival, and prognosis. In this study, to observe and explore the key targets and potential mechanisms of NSCLC resistance to GEM, we first cultured lung cancer CL1‐0 cells in a GEM‐containing medium to induce CL1‐0 cells to develop GEM resistance. Next, we compared protein expression between the parental and GEM‐R CL1‐0 cell groups. We observed significantly lower expression of autophagy‐related proteins in GEM‐R CL1‐0 cells than in parental CL1‐0 cells, indicating that autophagy is associated with GEM resistance in CL1‐0 cells. Furthermore, a series of autophagy experiments revealed that GEM‐R CL1‐0 cells had significantly reduced GEM‐induced c‐Jun N‐terminal kinase phosphorylation, which further affected the phosphorylation of Bcl‐2, thereby reducing the dissociation of Bcl‐2 and Beclin‐1 and ultimately reducing the generation of GEM‐induced autophagy‐dependent cell death. Our findings suggest that altering the expression of autophagy is a promising therapeutic option for drug‐resistant lung cancer.