Tea polyphenol epigallocatechin 3-gallate impedes the anti-apoptotic effects of low-grade repetitive stress through inhibition of Akt and NFkappaB survival pathways.
V79 Chinese Hamster lung fibroblasts were subjected to repetitive low-grade stress through multiple exposures to 30 microM H2O2 in culture for 4 weeks. Akt/protein kinase B became phosphorylated at serine473 and threonine308 during this period of repetitive stress. Concurrent exposure of the cells to LY294002 (5 microM), a phosphoinositide-3 kinase inhibitor or 4.5 microM epigallocatechin 3-gallate (EGCG), a tea polyphenol almost completely blocked Akt activation by repetitive stress. Phosphorylation of I kappa B kinase (IKK) and transcriptional activity driven by nuclear factor kappa B (NFkappaB) were significantly enhanced by repetitive oxidative stress. These increases were largely abolished by simultaneous exposure to EGCG. The repetitively stressed cells demonstrated a significant resistance to apoptosis by subsequent acute stress in the form of ultraviolet radiation at 5 J/m2 or H2O2 (7.5 mM). The resistance to apoptosis conferred by repetitive stress was drastically reduced (>80%) by constant exposure to EGCG during the stress period while the presence of LY294002 or the NFkappaB inhibitor SN50 brought about a relatively moderate effect (about 50-65%). Our data indicate that activation of Akt and NFkappaB pro-survival pathways by repetitive low-grade stress results in a strong inhibition of the normal apoptotic response after subsequent acute stress. The tea polyphenol EGCG impedes the activation of both Akt and NFkappaB by repetitive stress and as a result preserves the normal apoptotic response during subsequent acute stress.
Sen
Prosenjit
P
Crystallography and Molecular Biology Division, Saha Institute of Nuclear Physics, 1/AF Bidhan nagar, Kolkata 700064, India.
Chakraborty
Prabir Kumar
PK
Raha
Sanghamitra
S
D019870:1-Phosphatidylinositol 4-Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002392:Catechin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D010455:Peptides / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D013662:Tea / Q000737:chemistry*; D014466:Ultraviolet Rays / Q000009:adverse effects
D000975:Antioxidants; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D016328:NF-kappa B; D016877:Oxidants; D010455:Peptides; C118258:SN50 peptide; D013662:Tea; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D002392:Catechin; D006861:Hydrogen Peroxide; C045651:epigallocatechin gallate; D019870:1-Phosphatidylinositol 4-Kinase; D051057:Proto-Oncogene Proteins c-akt