Foxo3a expression and acetylation regulate cancer cell growth and sensitivity to cisplatin.
Many advanced cancers receive cisplatin-based chemotherapy. However, cisplatin resistance is a major obstacle for cancer chemotherapy. Foxo3a is a member of the Foxo transcription factor family, which modulates the expression of genes involved in DNA damage repair, apoptosis, and other cellular processes. In this study, we found that cisplatin-resistant cells were more sensitive to the anticancer agent mithramycin than their parental cells, and had a decreased level of Foxo3a expression. Foxo3a knockdown increased cell proliferation and resistance to cisplatin. On the other hand, mithramycin stimulated Foxo3a expression through reactive oxygen species production and sensitized cells to cisplatin, which was abolished by Foxo3a knockdown, while the acetylation status of Foxo3a was decreased in response to cisplatin treatment and was lower in cisplatin-resistant cells. Knockdown of Foxo3a-associated acetyltransferase p300 promoted cancer-cell growth and cisplatin resistance. In addition, non-acetylation-mimicking Foxo3a overexpression decreased cancer cell growth and sensitized cells to cisplatin less than wild-type Foxo3a overexpression. The current work may contribute to the evaluation of the therapeutic potential of inducing the Foxo3a pathway and acetylating the Foxo3a transcription factor, and lead to the reevaluation of cancer treatments based on mithramycin.
Shiota
Masaki
M
Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Yokomizo
Akira
A
Kashiwagi
Eiji
E
Tada
Yasuhiro
Y
Inokuchi
Junichi
J
Tatsugami
Katsunori
K
Kuroiwa
Kentaro
K
Uchiumi
Takeshi
T
Seki
Narihito
N
Naito
Seiji
S
D000107:Acetylation; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000032:analysis / Q000502:physiology*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008926:Plicamycin / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism
D000970:Antineoplastic Agents; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D017382:Reactive Oxygen Species; D008926:Plicamycin; D002945:Cisplatin