Resveratrol causes arrest in the S-phase prior to Fas-independent apoptosis in CEM-C7H2 acute leukemia cells.
Resveratrol (3,5,4'-trihydroxy-trans-stilbene), in the concentration range of 20 microM and above, induced arrest in the S-phase and apoptosis in the T cell-derived T-ALL lymphocytic leukemia cell line CEM-C7H2 which is deficient in functional p53 and p16. Expression of transgenic p16/INK4A, which causes arrest in G0/G1, markedly reduced the percentage of apoptotic cells. Antagonist antibodies to Fas or FasL, or constitutive expression of crmA did not diminish the extent of resveratrol-induced apoptosis. Furthermore, a caspase-8-negative, Fas-resistant Jurkat cell line was sensitive to resveratrol-induced apoptosis which could be strongly inhibited in the Jurkat as well as in the CEM cell line by z-VAD-fmk and z-IETD-fmk. The almost complete inhibition by z-IETD-fmk and the lack of inhibition by crmA suggested caspase-6 to be the essential initiator caspase. Western blots revealed the massive conversion of procaspase-6 to its active form, while caspase-3 and caspase-2 were proteolytically activated to a much lesser extent.
Bernhard
D
D
Institute of Medical Chemistry and Biochemistry, University of Innsbruck, A-6020 Innsbruck, Austria.
Tinhofer
I
I
Tonko
M
M
Hübl
H
H
Ausserlechner
M J
MJ
Greil
R
R
Kofler
R
R
Csordas
A
A
D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002469:Cell Separation; D004305:Dose-Response Relationship, Drug; D004318:Doxycycline / Q000494:pharmacology; D053222:Fas Ligand Protein; D005434:Flow Cytometry; D006801:Humans; D007399:Interphase / Q000187:drug effects; D019169:Jurkat Cells; D015459:Leukemia-Lymphoma, Adult T-Cell; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D000077185:Resveratrol; D016196:S Phase / Q000187:drug effects*; D013267:Stilbenes / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection; D019076:Transgenes / Q000235:genetics; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D000911:Antibodies, Monoclonal; D000972:Antineoplastic Agents, Phytogenic; D061945:Caspase Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D011993:Recombinant Fusion Proteins; D013267:Stilbenes; D019014:fas Receptor; D020169:Caspases; D004318:Doxycycline; D000077185:Resveratrol