The HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin modulates radiosensitivity by downregulating serine/threonine kinase 38 via Sp1 inhibition

Atsushi Enomoto, Takemichi Fukasawa, Nobuhiko Takamatsu, Michihiko Ito, Akinori Morita, Yoshio Hosoi, Kiyoshi Miyagawa

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

Abstract

The ansamycin-based HSP90 inhibitor 17-AAG (17-allylamino-17- demethoxygeldanamycin) combats tumors and has been shown to modulate cellular sensitivity to radiation, prompting researchers to use 17-AAG as a radiosensitizer. 17-AAG causes the degradation of several oncogenic and signaling proteins. We previously demonstrated that oxidative stress activates serine/threonine kinase 38 (STK38), a member of the protein kinase A (PKA)/PKG/PKC-like family. In the present study, we investigated how 17-AAG affects STK38 expression, and evaluated STK38's role in the regulation of radiosensitivity. We found that 17-AAG depleted cellular STK38 and reduced STK38's kinase activity. Importantly, 17-AAG downregulated the stk38 gene expression. Deletion analysis and site-directed mutagenesis experiments demonstrated that Sp1 was required for the stk38 promoter activity. Treatment with 17-AAG inhibited Sp1's binding to the stk38 promoter by decreasing the amount of Sp1 and knocking down Sp1 reduced STK38 expression. Moreover, 17-AAG treatment or STK38 knockdown enhanced the radiosensitivity of HeLa cells. Our data provide a novel mechanism, mediated by stk38 downregulation, by which 17-AAG radiosensitizes cells.

Original languageEnglish
Pages (from-to)3547-3558
Number of pages12
JournalEuropean Journal of Cancer
Volume49
Issue number16
DOIs
Publication statusPublished - 2013 Nov 1
Externally publishedYes

Keywords

  • 17-AAG
  • Radiosensitization
  • STK38
  • Sp1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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