Suppression of survivin phosphorylation on Thr34 by flavopiridol enhances tumor cell apoptosis.
Survivin is a member of the inhibitor of apoptosis gene family that is expressed in most human cancers and may facilitate evasion from apoptosis and aberrant mitotic progression. Here, exposure of breast carcinoma MCF-7 or cervical carcinoma HeLa cells to anticancer agents, including Adriamycin, Taxol, or UVB resulted in a 4-5-fold increased survivin expression. Changes in survivin levels after anticancer treatment did not involve modulation of survivin mRNA expression and were independent of de novo gene transcription. Conversely, inhibition of survivin phosphorylation on Thr(34) by the cyclin-dependent kinase inhibitor flavopiridol resulted in loss of survivin expression, and nonphosphorylatable survivin Thr(34)-->Ala exhibited accelerated clearance as compared with wild-type survivin. Sequential ablation of survivin phosphorylation on Thr(34) enhanced tumor cell apoptosis induced by anticancer agents independently of p53 and suppressed tumor growth without toxicity in a breast cancer xenograft model in vivo. These data suggest that Thr(34) phosphorylation critically regulates survivin levels in tumor cells and that sequential ablation of p34(cdc2) kinase activity may remove the survivin viability checkpoint and enhance apoptosis in tumor cells.
Wall
Nathan R
NR
Department of Cancer Biology and Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
O'Connor
Daniel S
DS
Plescia
Janet
J
Pommier
Yves
Y
Altieri
Dario C
DC
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001943:Breast Neoplasms / Q000473:pathology; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins; D017239:Paclitaxel / Q000494:pharmacology; D010766:Phosphorylation; D010769:Phosphothreonine / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics*; D000077022:Survivin; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays
D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D005419:Flavonoids; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D010880:Piperidines; D012333:RNA, Messenger; D000077022:Survivin; D010769:Phosphothreonine; C077990:alvocidib; D004317:Doxorubicin; D017239:Paclitaxel