5-Aza-2'-deoxycytidine restores proapoptotic function of p53 in cancer cells resistant to p53-induced apoptosis.
The expression of p53-target genes encoding the proapoptotic factor Noxa, but not PUMA, was not induced by p53 in HCT116 and SW480 cells, which show resistance to apoptosis in response to p53 overexpression. The lack of p53 inducibility of Noxa was restored by treatment with the DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine (5-aza-CdR). Furthermore, p53 induced apoptosis in HCT116 and SW480 cells treated with 5-aza-CdR. Moreover, the inhibition of Noxa expression by RNAi in 5-aza-CdR-treated HCT116 cells resulted in the partial inhibition of p53-induced apoptosis. These results suggest that epigenetic cancer therapy is possible for some cancers in combination with forced p53 activation.
Yagi
Shutaro
S
Department of Molecular Oncology, Institute of Gerontology, Nippon Medical School, Kanagawa, Japan.
Oda-Sato
Eri
E
Uehara
Ikuno
I
Asano
Yumi
Y
Nakajima
Wataru
W
Takeshita
Toshiyuki
T
Tanaka
Nobuyuki
N
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077209:Decitabine; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034622:RNA Interference; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D000964:Antimetabolites, Antineoplastic; D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C414742:P53AIP1 protein, human; C498702:PMAIP1 protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000077209:Decitabine; D015254:DNA Modification Methylases; D001374:Azacitidine