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Activator Protein 2 Status Determines the Chemosensitivity of Cancer Cells: Implications in Cancer Chemotherapy

¹ Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India and ² National Institute of Virology, Pune, India

Requests for reprints: Kumaravel Somasundaram, Department of Microbiology and Cell Biology, Indian Institute of Science, Sir C.V. Raman Road, Bangalore, Karnataka 560-012, India. Phone: 91-80-22932973; Fax: 91-80-23602697; E-mail: skumar{at}mcbl.iisc.ernet.in.

Cancer chemotherapeutic drugs induce apoptosis by several pathways. Inactivation of proapoptotic genes, or activation of survival signaling, leads to chemoresistance. Activator protein 2 (AP-2), a developmentally regulated sequence-specific DNA-binding transcription factor, has been shown to function like a tumor suppressor. Here, we show that controlled expression of AP-2, using tetracycline-inducible system, increased the chemosensitivity of cancer cells by severalfold by sensitizing cells to undergo apoptosis upon chemotherapy. Under these conditions, neither AP-2 expression nor drug treatment resulted in apoptosis induction, whereas in combination the cancer cells underwent massive apoptosis. We found that endogenous AP-2 protein is induced posttranscriptionally by various chemotherapeutic drugs. Blocking the endogenous AP-2 by small interfering RNA in human cancer cells lead to decreased apoptosis, increased colony formation, and chemoresistance irrespective of their p53 status upon chemotherapy. We further show that 5-aza-2'-deoxycytidine induced reexpression of AP-2 in MDA-MB-231 breast cancer cells (wherein AP-2 expression is silenced by hypermethylation), resulted in massive apoptosis induction, increased chemosensitivity, decreased colony formation, and loss of tumorigenesis upon chemotherapy. However, in MDA-MB-231 cells transfected with AP-2 small interfering RNA, 5-aza-2'-deoxycytidine treatment failed to increase apoptosis and chemosensitivity. The treatment also resulted in increased colony formation and efficient tumor formation upon chemotherapy. These results establish an important role for AP-2 in cancer cell chemosensitivity and provide new insights for modifying the chemosensitivity of cancer cells by activating apoptotic pathways.

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