Activator protein 2alpha status determines the chemosensitivity of cancer cells: implications in cancer chemotherapy.

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Wajapeyee N, Raut CG, Somasundaram K

Activator protein 2alpha status determines the chemosensitivity of cancer cells: implications in cancer chemotherapy.

Cancer Res. 2005 Oct 1;65(19):8628-34.

PubMed ID

16204029 [ View in PubMed

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Abstract

Cancer chemotherapeutic drugs induce apoptosis by several pathways. Inactivation of proapoptotic genes, or activation of survival signaling, leads to chemoresistance. Activator protein 2alpha (AP-2alpha), 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-2alpha, 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-2alpha expression nor drug treatment resulted in apoptosis induction, whereas in combination the cancer cells underwent massive apoptosis. We found that endogenous AP-2alpha protein is induced posttranscriptionally by various chemotherapeutic drugs. Blocking the endogenous AP-2alpha 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-2alpha in MDA-MB-231 breast cancer cells (wherein AP-2alpha 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-2alpha 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-2alpha in cancer cell chemosensitivity and provide new insights for modifying the chemosensitivity of cancer cells by activating apoptotic pathways.