Simultaneous targeting PI3K and PERK pathways promotes cell death and improves the clinical prognosis in esophageal squamous carcinoma

Biochem Biophys Res Commun. 2017 Nov 4;493(1):534-541. doi: 10.1016/j.bbrc.2017.08.156. Epub 2017 Sep 1.

Abstract

PI3K pathway is an important anti-tumor target, but its effect and mechanism is not clear in esophageal squamous cell carcinoma (ESCC). By analysis of the Cancer Genome Atlas (TCGA) datasets, we found that PI3Ks level were significantly upregulated in human esophageal cancer tissues compared with that in non-cancer tissues. The alteration of PI3K can significantly affect the overall patient survival in ESCC but not in esophageal adenocarcinoma (EAC). We found that the classic PI3K inhibitor LY294002 obviously inhibited the canonical mammalian target of rapamycin (mTOR) pathway and restrained the growth of ESCC with less toxicity to normal cells. Besides, LY294002 inhibited noncanonical PKR-like ER kinase (PERK)/elF2α/ATF4 pathway as well. Both siRNA and the small molecule inhibitor GSK2656157 against PERK/elF2α/ATF4 pathway can significantly inhibit the growth of ESCC. More importantly, GSK2656157 aggravated the inhibitory effect of LY294002 on cell growth, colony formation, and apoptosis induction of ESCC. In addition of dual high expression of PI3K and PERK pathways in the ESCC patients, the difference of overall survival (OS) was more significant than using PI3K alone. These results indicated that dual targeting of PI3K and PERK pathways might improve clinical prognosis and enhance the treatment of ESCC patients.

Keywords: ESCC; GSK2656157; LY294002; PERK; PI3K; mTOR.

MeSH terms

  • Adenine / administration & dosage
  • Adenine / analogs & derivatives*
  • Aged
  • Antineoplastic Agents / administration & dosage
  • Apoptosis / drug effects*
  • Carcinoma, Squamous Cell / drug therapy*
  • Carcinoma, Squamous Cell / metabolism*
  • Carcinoma, Squamous Cell / mortality
  • China / epidemiology
  • Esophageal Neoplasms / drug therapy*
  • Esophageal Neoplasms / metabolism*
  • Esophageal Neoplasms / mortality
  • Esophageal Squamous Cell Carcinoma
  • Female
  • Humans
  • Indoles / administration & dosage*
  • Male
  • Middle Aged
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Prevalence
  • Prognosis
  • Signal Transduction / drug effects*
  • Survival Rate
  • Treatment Outcome
  • eIF-2 Kinase / antagonists & inhibitors
  • eIF-2 Kinase / metabolism*

Substances

  • Antineoplastic Agents
  • GSK2656157
  • Indoles
  • Phosphoinositide-3 Kinase Inhibitors
  • EIF2AK3 protein, human
  • eIF-2 Kinase
  • Adenine