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

Tumour Biol. 2016 Jul;37(7):9789-96. doi: 10.1007/s13277-016-4877-5. Epub 2016 Jan 25.

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.

Keywords: Autophagy; Cervical cancer; Chemotherapy; ERK; GRIM-19; HIF-1a.

Publication types

  • Comparative Study

MeSH terms

  • Adult
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Apoptosis / drug effects
  • Apoptosis Regulatory Proteins / antagonists & inhibitors
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Autophagy / drug effects*
  • Biomarkers, Tumor / metabolism
  • Blotting, Western
  • Case-Control Studies
  • Cell Proliferation / drug effects
  • Drug Resistance, Neoplasm
  • Female
  • Fluorescent Antibody Technique
  • Follow-Up Studies
  • HeLa Cells
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Lymphatic Metastasis
  • Male
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • NADH, NADPH Oxidoreductases / antagonists & inhibitors
  • NADH, NADPH Oxidoreductases / genetics
  • NADH, NADPH Oxidoreductases / metabolism*
  • Neoplasm Invasiveness
  • Neoplasm Staging
  • Paclitaxel / pharmacology
  • Prognosis
  • RNA, Small Interfering / genetics
  • STAT3 Transcription Factor / metabolism*
  • Survival Rate
  • Tumor Cells, Cultured
  • Uterine Cervical Neoplasms / drug therapy
  • Uterine Cervical Neoplasms / metabolism
  • Uterine Cervical Neoplasms / pathology*

Substances

  • Antineoplastic Agents, Phytogenic
  • Apoptosis Regulatory Proteins
  • Biomarkers, Tumor
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • RNA, Small Interfering
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • NADH, NADPH Oxidoreductases
  • NDUFA13 protein, human
  • MAPK1 protein, human
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Paclitaxel