A novel apoptosis-inducing mechanism of 5-aza-2'-deoxycitidine in melanoma cells: Demethylation of TNF-α and activation of FOXO1.
Melanoma is a poor-prognosis cancer in both humans and dogs, and so the anti-tumor effects of 5-aza-2'-deoxycitidine (5-aza) on solid tumors such as melanoma have gained much attention. However, its anti-tumor mechanism remains entirely unclear. This present study revealed a part of the anti-tumor effects of 5-aza, focusing on apoptosis induction, on human and canine melanoma cells. Treatment with 5-aza markedly induced obvious apoptosis in melanoma cells. 5-Aza-induced apoptosis was possibly due to induced expression of cytotoxic cytokines such as TNF-α. We revealed hypermethylation of the promoter region of TNF-α as a consequence of treatment with 5-aza. Concurrently, we evaluated the effect of 5-aza on the Akt/FOXO1 signaling cascade, which plays a pivotal role in the transcription of cytokine genes. As a result, 5-aza inactivated Akt and inversely activated FOXO1, which contributed to the up-regulation of TNF-α. Furthermore, up-regulation of TNF-α by 5-aza administration was found in in vivo experiments. These current data suggest a novel apoptosis-inducing mechanism of 5-aza and indicate that 5-aza could be a promising therapeutic agent for the treatment of human and canine melanomas.
Laboratory of Molecular Diagnostics and Therapeutics, Joint Faculty of Veterinary Medicine, Yamaguchi University, 1677-1 Yoshida, Yamaguchi 753-8515, Japan; Biomedical Science Center for Translational Research, The United Graduate School of Veterinary Science, Yamaguchi University, 1677-1 Yoshida, Yamaguchi 753-8515, Japan. Electronic address: snoguchi@yamaguchi-u.ac.jp.
Shunsuke
S
Noguchi
Laboratory of Veterinary Clinical Oncology, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
Takashi
T
Mori
The United Graduate School of Veterinary Science, Yamaguchi University, 1677-1 Yoshida, Yamaguchi 753-8515, Japan.
Masaya
M
Igase
Laboratory of Molecular Diagnostics and Therapeutics, Joint Faculty of Veterinary Medicine, Yamaguchi University, 1677-1 Yoshida, Yamaguchi 753-8515, Japan; Biomedical Science Center for Translational Research, The United Graduate School of Veterinary Science, Yamaguchi University, 1677-1 Yoshida, Yamaguchi 753-8515, Japan.
Takuya
T
Mizuno
D000818:Animals; D017209:Apoptosis; D001374:Azacitidine / Q000378:metabolism* / Q000494:pharmacology; D045744:Cell Line, Tumor; D019175:DNA Methylation; D004285:Dogs; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011379:Prognosis; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism
C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D001374:Azacitidine
5-aza-2′-deoxycitidine; Apoptosis; FOXO1; Melanoma; TNF-α