Wajapeyee, Narendra and Raut, Chandrashekhar Ganpat and Somasundaram, Kumaravel (2005) Activator Protein 2$\alpha$ Status Determines the Chemosensitivity of Cancer Cells: Implications in Cancer Chemotherapy. In: Cancer Research, 65 (19). pp. 8628-8634.
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Cancer chemotherapeutic drugs induce apoptosis by several pathways. Inactivation of proapoptotic genes, or activation of survival signaling, leads to chemoresistance. Activator protein 2$\alpha$ (AP-2$\alpha$), 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$\alpha$, 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$\alpha$ expression nor drug treatment resulted in apoptosis induction, whereas in combination the cancer cells underwent massive apoptosis. We found that endogenous AP-2$\alpha$ protein is induced posttranscriptionally by various chemotherapeutic drugs. Blocking the endogenous AP-2$\alpha$ 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$\alpha$ in MDA-MB-2$\alpha$31 breast cancer cells (wherein AP-2$\alpha$ 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$\alpha$ 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$\alpha$ in cancer cell chemosensitivity and provide new insights for modifying the chemosensitivity of cancer cells by activating apoptotic pathways.
|Item Type:||Journal Article|
|Additional Information:||The Copyright belongs to American Association for Cancer Research.|
|Department/Centre:||Division of Biological Sciences > Microbiology & Cell Biology|
|Date Deposited:||22 Mar 2006|
|Last Modified:||19 Sep 2010 04:23|
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