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

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Tumor Biology

Abstract

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.

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Acknowledgments

This study was funded by Wuhan Yellow Crane Medical Talent Program Grant No. 2015-12 and by the supporting program of the Ministry of Human Resource of China Oversea Returned scholars, and the National Natural Science Foundation of China (Grant No. 81572608).

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Authors and Affiliations

  1. Clinical Research Center, Wuhan Medical and Healthcare Center for Women and Children, No. 100 Hongkong Rd, Wuhan, Hubei, China

    Xin Yue, Peiwei Zhao & Xuelian He

  2. Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, China

    Kongming Wu

  3. Department of Pathology, Wuhan Medical and Healthcare Center for Women and Children, Wuhan, Hubei, China

    Juan Huang & Wen Zhang

  4. School of Public Health, Wuhan University, Wuhan, China

    Yaogui Wu

  5. Department of Oncology, Renmin Hospital, Wuhan University, Wuhan, China

    Xiaohui Liang

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  1. Xin Yue
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  2. Peiwei Zhao
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  4. Juan Huang
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  5. Wen Zhang
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  8. Xuelian He
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Correspondence to Xuelian He.

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Xin Yue and Peiwei Zhao have contributed equally.

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Yue, X., Zhao, P., Wu, K. et al. GRIM-19 inhibition induced autophagy through activation of ERK and HIF-1α not STAT3 in Hela cells. Tumor Biol. 37, 9789–9796 (2016). https://doi.org/10.1007/s13277-016-4877-5

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  • DOI: https://doi.org/10.1007/s13277-016-4877-5

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