Opa-interacting protein 5 modulates docetaxel-induced cell death via regulation of mitophagy in gastric cancer

Tumour Biol. 2017 Oct;39(10):1010428317733985. doi: 10.1177/1010428317733985.

Abstract

Damage to mitochondria induces mitophagy, a cellular process that is gaining interest for its therapeutic relevance to a variety of human diseases. However, the mechanism underlying mitochondrial depolarization and clearance in mitophagy remains poorly understood. We previously reported that mitochondria-induced cell death was caused by knockdown of Neisseria gonorrhoeae opacity-associated-interacting protein 5 in gastric cancer. In this study, we show that Neisseria gonorrhoeae opacity-associated-interacting protein 5 loss and gain of function modulates mitophagy induced by treatment with docetaxel, a chemotherapy drug for gastric cancer. The activation of mitophagy by Neisseria gonorrhoeae opacity-associated-interacting protein 5 overexpression promoted cell survival, preventing docetaxel-induced mitochondrial clearance. Conversely, short interfering RNA-mediated knockdown of Neisseria gonorrhoeae opacity-associated-interacting protein 5 accelerated docetaxel-induced apoptosis while increasing mitochondrial depolarization, reactive oxygen species, and endoplasmic reticulum stress and decreasing adenosine triphosphate production. We also found that the mitochondrial outer membrane proteins mitofusin 2 and phosphatase and tensin homolog-induced putative kinase 1 colocalized with Neisseria gonorrhoeae opacity-associated-interacting protein 5 in mitochondria and that mitofusin 2 knockdown altered Neisseria gonorrhoeae opacity-associated-interacting protein 5 expression. These findings indicate that Neisseria gonorrhoeae opacity-associated-interacting protein 5 modulates docetaxel-induced mitophagic cell death and therefore suggest that this protein comprises a potential therapeutic target for gastric cancer treatment.

Keywords: Opa-interacting protein 5; cell death; docetaxel; mitochondrial depolarization; mitophagy.

MeSH terms

  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Cell Cycle Proteins
  • Cell Death / drug effects*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Chromosomal Proteins, Non-Histone / metabolism*
  • Docetaxel
  • GTP Phosphohydrolases / metabolism
  • Humans
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Mitochondrial Proteins / metabolism
  • Mitophagy / drug effects
  • Mitophagy / physiology*
  • Neisseria gonorrhoeae / metabolism
  • Phosphoric Monoester Hydrolases / metabolism
  • RNA, Small Interfering / metabolism
  • Reactive Oxygen Species / metabolism
  • Stomach Neoplasms / metabolism*
  • Taxoids / pharmacology*
  • Tensins / metabolism

Substances

  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • Mitochondrial Proteins
  • OIP5 protein, human
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • Taxoids
  • Tensins
  • Docetaxel
  • Phosphoric Monoester Hydrolases
  • GTP Phosphohydrolases
  • MFN2 protein, human