Insulin-like growth factor 1 receptor-mediated cell survival in hypoxia depends on the promotion of autophagy via suppression of the PI3K/Akt/mTOR signaling pathway

Mol Med Rep. 2017 Apr;15(4):2136-2142. doi: 10.3892/mmr.2017.6265. Epub 2017 Mar 1.

Abstract

Hypoxia is widely accepted as a fundamental biological phenomenon, which is strongly associated with tissue damage and cell viability under stress conditions. Insulin-like growth factor‑1 (IGF‑1) is known to protect tissues from multiple types of damage, and protect cells from apoptosis. Hypoxia is a regulatory factor of the IGF system, however the role of the IGF-1 receptor (IGF‑1R) in hypoxia‑induced apoptosis remains unclear. The present study investigated the potential mechanisms associated with IGF‑1R‑associated apoptosis under hypoxic conditions. Mouse embryonic fibroblasts exhibiting disruption or overexpression of IGF‑1R (R‑ cells and R+ cells) were used to examine the level of apoptosis, autophagy, and production of reactive oxygen species (ROS). The autophagy inhibitor 3‑methyladenine was used to assess the effect of autophagy on ROS production and apoptosis under hypoxic conditions. A potential downstream signaling pathway involving phosphatidylinositol 3-kinase (PI3K)/threonine protein kinase B (Akt)/mammalian target of rapamycin (mTOR) was identifiedby western blot analysis. The results demonstrated that hypoxia induced apoptosis, increased ROS production, and promoted autophagy in a time‑dependent manner relative to that observed under normoxia. R+ cells exhibited a lower percentage of apoptotic cells, lower ROS production, and higher levels of autophagy when compared to that of R- cells. In addition, inhibition of autophagy led to increased ROS production and a higher percentage of apoptotic cells in the two cell types. Furthermore, IGF‑1R is related with PI3K/Akt/mTOR signaling pathway and enhanced autophagy-associated protein expression, which was verified following treatment with the PI3K inhibitor LY294002. These results indicated that IGF‑1R may increase cell viability under hypoxic conditions by promoting autophagy and scavenging ROS production, which is closed with PI3K/Akt/mTOR signaling pathway.

MeSH terms

  • Animals
  • Apoptosis
  • Autophagy*
  • Cell Hypoxia
  • Cell Line
  • Cell Survival*
  • Fibroblasts / cytology
  • Fibroblasts / metabolism*
  • Hypoxia / metabolism*
  • Mice
  • Phosphatidylinositol 3-Kinase / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Reactive Oxygen Species / metabolism
  • Receptor, IGF Type 1 / metabolism*
  • Signal Transduction*
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Reactive Oxygen Species
  • Phosphatidylinositol 3-Kinase
  • Receptor, IGF Type 1
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases