Oleanolic acid induces protective autophagy in cancer cells through the JNK and mTOR pathways

Abstract

Autophagy is a biological process that eliminates damaged or excessive proteins and is utilized by various types of cells to maintain cellular homeostasis. Autophagy also occurs in cancer cells and exerts anti-survival or pro-survival effects depending on stimuli, nutrient and context. Oleanolic acid (OA), a widely spread natural compound, induces apoptosis in a range of cancer cells. However, some tumor cell lines are resistant to the pro-apoptotic effect of OA, and the mechanism remains unknown. In the present study, we found that OA induced autophagic event in cancer cells in a dose- and time-dependent manner, evidenced by an increased ratio between LC3-II and LC3-I and frequent granulation of LC3 proteins in OA-stimulated tumor cell lines. Inhibition of autophagy potentiated the pro-apoptotic activity of OA on cancer cells. Furthermore, the JNK and mTOR signaling pathways were found to be affected by OA treatment. Interfering with JNK and mTOR abolished OA-induced autophagy and sensitized cancer cells to apoptosis. Collectively, we showed that OA was able to initiate protective autophagy, which compromised the antitumor activity of OA on cancer cells. Blocking autophagy may be a promising strategy to enhance the tumor suppressor activity of OA.