Endoplasmic reticulum stress induces 5-fluorouracil resistance in human colon cancer cells

Environ Toxicol Pharmacol. 2016 Jun:44:128-33. doi: 10.1016/j.etap.2016.05.005. Epub 2016 May 4.

Abstract

Colon cancer can be treated with 5-fluorouracil (5-FU), but 5-FU resistance frequently occurs. We determined whether 5-FU resistance arises as a result of endoplasmic reticulum (ER) stress. 5-FU-resistant SNUC5 colon cancer cells (SNUC5/FUR cells) expressed higher levels of ER stress-related proteins than drug-sensitive SNUC5 cells. SNUC5/FUR cells also exhibited more intense ER staining and higher level of mitochondrial Ca(2+) overload. SNUC5/FUR cells transfected with siRNA against GRP78, ATF6, ERK, or AKT were more sensitive to 5-FU than siControl RNA-transfected cells. These results suggested that 5-FU resistance was associated with ER stress in colon cancer.

Keywords: 5-FU resistance; ER stress; ER stress-related proteins; Extracellular signal-regulated kinases; Human colon cancer cells.

MeSH terms

  • Activating Transcription Factor 6 / genetics
  • Antimetabolites, Antineoplastic / pharmacology*
  • Calcium / metabolism
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Colonic Neoplasms / metabolism
  • Drug Resistance, Neoplasm*
  • Endoplasmic Reticulum Chaperone BiP
  • Endoplasmic Reticulum Stress*
  • Extracellular Signal-Regulated MAP Kinases / genetics
  • Fluorouracil / pharmacology*
  • Gene Knockdown Techniques
  • Heat-Shock Proteins / genetics
  • Humans
  • Mitochondria / metabolism
  • Proto-Oncogene Proteins c-akt / genetics
  • RNA, Small Interfering / genetics

Substances

  • ATF6 protein, human
  • Activating Transcription Factor 6
  • Antimetabolites, Antineoplastic
  • Endoplasmic Reticulum Chaperone BiP
  • HSPA5 protein, human
  • Heat-Shock Proteins
  • RNA, Small Interfering
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • Calcium
  • Fluorouracil