GRIM-19 inhibition induced autophagy through activation of ERK and HIF-1α not STAT3 in Hela cells

作者：Yue, Xin; Zhao, Peiwei; Wu, Kongming; Huang, Juan; Zhang, Wen; Wu, Yaogui; Liang, Xiaohui; He, Xuelian^*

来源：Tumor Biology, 2016, 37(7): 9789-9796.

DOI：10.1007/s13277-016-4877-5

• GRIM-19
• Autophagy
• Cervical cancer
• Chemotherapy
• ERK
• HIF-1a

Gene associated with retinoid-interferon-induced mortality (GRIM-19), an important subunit of mitochondrial complex I, has been identified as a tumor suppressor, and its reduced expression has been reported to be associated with tumorigenesis and metastasis. Autophagy has been proposed as a protective mechanism for cell survival under various stresses, including chemotherapy. However, it remains unknown whether GRIM-19 is linked to autophagy and chemotherapy resistance. Here, we showed that suppression of GRIM-19 by shRNA enhanced cell-type-dependent autophagy by activating extracellular regulated protein kinase (ERK) and hypoxia inducible factor-1a (HIF-1a) in a reactive oxygen species (ROS)-mediated manner, and thereby conferred resistance to paclitaxel. Besides, the antioxidant N-acetyl-l-cysteine (NAC) and autophagy inhibitor 3-MA could in part overcome this resistance. We also found that GRIM-19 expression was significantly correlated with clinical stage and grade in patients with cervical cancers. Taken together, our results indicated that GRIM-19 inhibition induced autophagy and chemotherapy resistance, which could affect prognosis of cervical cancers. Our study has identified new function of GRIM-19 and its underlying mechanism, and it will provide possible avenues for therapeutic targeting in cervical cancers.

• 出版日期2016-7
• 单位武汉大学; 华中科技大学