Glucose deprivation-induced endoplasmic reticulum stress response plays a pivotal role in enhancement of TRAIL cytotoxicity

Kalishwaralal Kalimuthu, Jin Hong Kim, Yong Seok Park, Xu Luo, Lin Zhang, Ja Lok Ku, M. Haroon A. Choudry, Yong J. Lee

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Abnormalities of the tumor vasculature result in insufficient blood supply and development of a tumor microenvironment that is characterized by low glucose concentrations, low extracellular pH, and low oxygen tensions. We previously reported that glucose-deprived conditions induce metabolic stress and promote tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cytotoxicity. In this study, we examined whether the metabolic stress-associated endoplasmic reticulum (ER) stress response pathway plays a pivotal role in the enhancement of TRAIL cytotoxicity. We observed no significant cytotoxicity when human colorectal cancer SW48 cells were treated with various doses of TRAIL (2–100 ng/ml) for 4 h or glucose (0–25 mM) for 24 h. However, a combination of TRAIL and low glucose-induced dose-dependent apoptosis through activation of caspases (-8, -9, and -3). Studies with activating transcription factor 4 (ATF4), C/EBP-homologous protein (CHOP), p53 upregulated modulator of apoptosis (PUMA), or death receptor 5 (DR5)-deficient mouse embryonic fibroblasts or HCT116 cells suggest that the ATF4–CHOP–PUMA axis and the ATF4–CHOP–DR5 axis are involved in the combined treatment-induced apoptosis. Moreover, the combined treatment-induced apoptosis was completely suppressed in BH3 interacting-domain death agonist (Bid)- or Bcl-2-associated X protein (Bax)-deficient HCT116 cells, but not Bak-deficient HCT116 cells. Interestingly, the combined treatment-induced Bax oligomerization was suppressed in PUMA-deficient HCT116 cells. These results suggest that glucose deprivation enhances TRAIL-induced apoptosis by integrating the ATF4–CHOP–PUMA axis and the ATF4–CHOP–DR5 axis, consequently amplifying the Bid–Bax-associated mitochondria-dependent pathway.

Original languageEnglish (US)
Pages (from-to)6666-6677
Number of pages12
JournalJournal of Cellular Physiology
Issue number9
StatePublished - Sep 2021


  • TRAIL cytotoxicity
  • endoplasmic reticulum stress
  • glucose deprivation

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology


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