Foxo3a expression and acetylation regulate cancer cell growth and sensitivity to cisplatin

Masaki Shiota, Akira Yokomizo, Eiji Kashiwagi, Yasuhiro Tada, Junichi Inokuchi, Katsunori Tatsugami, Kentaro Kuroiwa, Takeshi Uchiumi, Narihito Seki, Seiji Naito

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1177-1185
Number of pages9
JournalCancer Science
Volume101
Issue number5
DOIs
Publication statusPublished - May 1 2010

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Acetylation
Cisplatin
Growth
Plicamycin
Neoplasms
Transcription Factors
Drug Therapy
DNA Repair
Antineoplastic Agents
DNA Damage
Reactive Oxygen Species
Therapeutics
Cell Proliferation
Apoptosis
Gene Expression

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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Foxo3a expression and acetylation regulate cancer cell growth and sensitivity to cisplatin. / Shiota, Masaki; Yokomizo, Akira; Kashiwagi, Eiji; Tada, Yasuhiro; Inokuchi, Junichi; Tatsugami, Katsunori; Kuroiwa, Kentaro; Uchiumi, Takeshi; Seki, Narihito; Naito, Seiji.

In: Cancer Science, Vol. 101, No. 5, 01.05.2010, p. 1177-1185.

Research output: Contribution to journalArticle

Shiota, Masaki ; Yokomizo, Akira ; Kashiwagi, Eiji ; Tada, Yasuhiro ; Inokuchi, Junichi ; Tatsugami, Katsunori ; Kuroiwa, Kentaro ; Uchiumi, Takeshi ; Seki, Narihito ; Naito, Seiji. / Foxo3a expression and acetylation regulate cancer cell growth and sensitivity to cisplatin. In: Cancer Science. 2010 ; Vol. 101, No. 5. pp. 1177-1185.
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