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GRP78 Regulates Apoptosis, Cell Survival and Proliferation in 5-Fluorouracil-resistant SNUC5 Colon Cancer Cells.

Abstract
5-Fluorouracil (5-FU) is an effective anticancer drug. However, the development of drug resistance has limited its chemotherapeutic efficacy. To address this problem, we investigated the expression of glucose-regulated protein (GRP78, 78 kDa) in 5-FU-resistant colorectal cancer (CRC) cells (SNUC5/5FUR). GRP78 was highly expressed in the SNUC5/5FUR cells compared to wild-type SNUC5 cells. In the presence of 5-FU, GRP78 knockdown induced apoptosis via activation of caspase-3 and poly(ADP-ribose)-polymerase 1. GRP78 also inhibited the production of intracellular reactive oxygen species by regulating stress-associated signaling pathways. Furthermore, GRP78 enhanced cell survival and proliferation via activation of the phosphatidylinosito-3-kinase-AKT-mammalian target of rapamycin axis and cell cycle-associated proteins. These effects were blocked upon GRP78 knockdown, which indicates that GRP78 is involved in the development of 5-FU resistance in these CRC cells. Therefore, a combination of chemotherapy and GRP78-specific targeting may counteract 5-FU resistance in CRC cells.
AuthorsJun Hee Lee, Yeo Min Yoon, Sang Hun Lee
JournalAnticancer research (Anticancer Res) Vol. 37 Issue 9 Pg. 4943-4951 (09 2017) ISSN: 1791-7530 [Electronic] Greece
PMID28870916 (Publication Type: Journal Article)
CopyrightCopyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
Chemical References
  • Antimetabolites, Antineoplastic
  • Endoplasmic Reticulum Chaperone BiP
  • HSPA5 protein, human
  • Heat-Shock Proteins
  • RNA, Small Interfering
  • Fluorouracil
Topics
  • Antimetabolites, Antineoplastic (pharmacology)
  • Apoptosis (drug effects)
  • Cell Proliferation (drug effects)
  • Cell Survival (drug effects)
  • Colonic Neoplasms (drug therapy, metabolism, pathology)
  • Drug Resistance, Neoplasm
  • Endoplasmic Reticulum Chaperone BiP
  • Fluorouracil (pharmacology)
  • Heat-Shock Proteins (antagonists & inhibitors, genetics, metabolism)
  • Humans
  • RNA, Small Interfering (genetics)
  • Tumor Cells, Cultured

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