Activator protein 2alpha status determines the chemosensitivity of cancer cells: implications in cancer chemotherapy.
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.
Wajapeyee
Narendra
N
Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India and National Institute of Virology, Pune, India.
Raut
Chandrashekhar Ganpat
CG
Somasundaram
Kumaravel
K
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D019175:DNA Methylation; D000077209:Decitabine; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050656:Transcription Factor AP-2 / Q000096:biosynthesis* / Q000235:genetics
D000964:Antimetabolites, Antineoplastic; D034741:RNA, Small Interfering; D050656:Transcription Factor AP-2; D000077209:Decitabine; D001374:Azacitidine