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

Autor: Yong Seok Park, Kalishwaralal Kalimuthu, Yong J. Lee, Ja Lok Ku, Jin Hong Kim, Xu Luo, Lin Zhang, M. Haroon A. Choudry
Rok vydání: 2021
Předmět:
0301 basic medicine
Physiology
Clinical Biochemistry
Apoptosis
Models
Biological
TNF-Related Apoptosis-Inducing Ligand
03 medical and health sciences
0302 clinical medicine
Cell Line
Tumor
Proto-Oncogene Proteins
Humans
p53 upregulated modulator of apoptosis
Cytotoxicity
Caspase
bcl-2-Associated X Protein
Tumor microenvironment
biology
Chemistry
Endoplasmic reticulum
ATF4
Cell Biology
Endoplasmic Reticulum Stress
Activating Transcription Factor 4
Mitochondria
Cell biology
Enzyme Activation
Glucose
bcl-2 Homologous Antagonist-Killer Protein
030104 developmental biology
Caspases
030220 oncology & carcinogenesis
biology.protein
Tumor necrosis factor alpha
biological phenomena
cell phenomena
and immunity
Apoptosis Regulatory Proteins
Transcription Factor CHOP
BH3 Interacting Domain Death Agonist Protein
Signal Transduction
Zdroj: Journal of Cellular Physiology. 236:6666-6677
ISSN: 1097-4652
0021-9541
Popis: 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.
Databáze: OpenAIRE
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