Survivin and escaping in therapy-induced cellular senescence.
Therapy-induced accelerated cellular senescence (ACS) is a reversible tumor response to chemotherapy that is likely detrimental to the overall therapeutic efficacy of cancer treatment. To further understand the mechanism by which cancer cells can escape the sustained cell cycle arrest in ACS, we established a tissue culture model, in which the p53-null NCI-H1299 cells can be induced into senescence by an abbreviated exposure to a chemotherapeutic agent. Previously, we have reported that senescent cells overexpress Cdc2/Cdk1 when they bypassed the prolonged arrest and their viability is dependent on Cdc2/Cdk1 kinase activity. In our study, we show that human survivin is the immediate downstream effector of the Cdc2/Cdk1 mediated survival signal. Survivin cooperates with Cdc2/Cdk1 to inhibit apoptosis following chemotherapy and promote senescence escape. Using HIV-1 TAT peptides to disrupt survivin phosphorylation by Cdc2/Cdk1, we also found that phosphorylated survivin is necessary both for the escape of senescent cells and for maintenance of subsequent viability after bypassing senescence. These results further propose survivin as an important determinant of senescence reversibility and as a putative molecular target to enforce cell death in ACS.
Wang
Qin
Q
Seattle Institute for Biomedical and Clinical Research, VA Puget Sound Health Care System, Seattle, Washington. proteinss@hotmail.com
Wu
Peter C
PC
Roberson
Rachel S
RS
Luk
Belinda V
BV
Ivanova
Iana
I
Chu
Elizabeth
E
Wu
Daniel Y
DY
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D016203:CDC2 Protein Kinase / Q000378:metabolism; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D019926:Cyclin B / Q000378:metabolism; D018844:Cyclin-Dependent Kinases; D015696:Gene Products, tat / Q000378:metabolism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000737:chemistry; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000378:metabolism; D000077022:Survivin
D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D019926:Cyclin B; D015696:Gene Products, tat; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D016376:Oligonucleotides, Antisense; D034741:RNA, Small Interfering; D000077022:Survivin; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases