Prostaglandin E1 reduces the keratinocyte toxicity of sorafenib by maintaining signal transducer and activator of transcription 3 (STAT3) activity and enhancing the cAMP response element binding protein (CREB) activity

• Shichiri, Hiroaki

• Yamamoto, Kazuhiro

• Tokura, Maya

• Ishida, Takahiro

• Uda, Atsushi

• Bito, Toshinori

• Nishigori, Chikako

• Nakagawa, Tsutomu

• Hirano, Takeshi

• Yano, Ikuko

• Hirai, Midori

Abstract

Hand-foot skin reaction (HFSR) is a common side effect of multiple tyrosine kinase inhibitors (mTKIs). HFSR can necessitate dose reductions or interruption of therapy owing to its negative effect on the quality of life. Therefore, effective use of mTKIs requires measures to prevent HFSR. We evaluated the effect of prostaglandin El (PGE(1)) on HFSR, because PGE(1) is already used to treat bed sores and skin ulcers and has established angiogenic and antiproliferative effects in keratinocytes. We found that the pathogenesis of sorafenib-induced HFSR is characterized by a decrease in levels of a phosphorylated signal transducer and activator of transcription 3 (STAT3). We investigated the effect of PGE(1) on the sorafenib-mediated reduction in phosphorylated STAT3 levels in HaCaT human epidermal keratinocytes. In cells treated with sorafenib, phosphorylated STAT3 levels decreased in a concentration-dependent manner, and this effect was blocked in cells treated with sorafenib and PGE(1). Furthermore, the expression of phosphorylated STAT3, the antiapoptotic proteins myeloid cell leukemia-1 (Mcl-1) and survivin decreased in cells pretreated with an inhibitor of CAMP response element binding protein (CREB). Cell viability increased in cells treated with sorafenib and PGE(1) compared with that in cells treated with sorafenib alone, and these effects were not observed in STAT3 knockdown HaCaT cells. Collectively, these findings indicate that PGE1 blocks the inhibitory effects of sorafenib on cell growth by maintaining the activity of STAT3 and enhancing the CREB activity. Therefore, PGE(1) might represent an effective treatment for the prevention of sorafenib-induced HFSR.

Journal

• Biochemical and Biophysical Research Communications

  Biochemical and Biophysical Research Communications 485 (2), 227-233, 2017-04-01

  Elsevier

Keywords

• Sorafenib
• Prostaglandin E1
• STAT3
• Keratinocyte
• Hand-foot skin reaction

Details

• CRID: 1050012570392521472
• NII Article ID: 120006733140
• NII Book ID: AA00564395
• DOI: 10.1016/j.bbrc.2017.02.107
• ISSN: 10902104
• ISSN: 0006291X
• HANDLE: 20.500.14094/90006403
• Web Site: https://api.elsevier.com/content/article/PII:S0006291X17303984?httpAccept=text/xml
• Web Site: https://api.elsevier.com/content/article/PII:S0006291X17303984?httpAccept=text/plain
• Text Lang: en
• Article Type: journal article
• Data Source:
  • IRDB
  • Crossref
  • CiNii Articles
  • KAKEN