Overexpression of the dual specificity phosphatase, Cdc25C, confers sensitivity on tumor cells to doxorubicin-induced cell death.
Cdc25C is a dual-specificity phosphatase that is involved in induction of mitosis by removal of the inhibitory phosphates from cyclin-dependent kinase 1/cyclin B. In this study, adenovirus-mediated overexpression of Cdc25C sensitizes U2OS tumor cells to doxorubicin-induced apoptosis. U2OS cells that stably overexpress Cdc25C are also sensitized to doxorubicin-induced cell death. These cells show reduced phosphorylation of cyclin-dependent kinase 1 on Tyr15 and impaired up-regulation of p21 in response to treatment with doxorubicin. In contrast to doxorubicin, overexpression of Cdc25C does not confer sensitivity to apoptosis on treatment with 5-fluorouracil or hydroxyurea. This sensitization of tumor cells to doxorubicin-induced cell death by overexpression of Cdc25C is not p53 dependent. Intriguingly, nontransformed MCF10A cells are not sensitized to doxorubicin treatment by overexpression of Cdc25C nor does the lack of Cdc25C affect cell cycle progression or the G2 arrest caused by doxorubicin. These results support the idea that a combination of overexpressing Cdc25C with treatment with conventional genotoxic agents should be given serious considerations as a novel therapeutic strategy.
Varmeh
Shohreh
S
Department of Oncological Sciences, Mount Sinai School of Medicine, Box 1130, New York, NY 10029, USA.
Manfredi
James J
JJ
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D002453:Cell Cycle; D016923:Cell Death; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology*; D054637:Dual-Specificity Phosphatases / Q000378:metabolism; D005472:Fluorouracil / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000378:metabolism; D020687:cdc25 Phosphatases / Q000378:metabolism / Q000502:physiology*
D000903:Antibiotics, Antineoplastic; D034741:RNA, Small Interfering; D004317:Doxorubicin; C517009:CDC25C protein, human; D054637:Dual-Specificity Phosphatases; D020687:cdc25 Phosphatases; D005472:Fluorouracil; D006918:Hydroxyurea