Heat shock protein 90 is a potential therapeutic target in cholangiocarcinoma

Tomoki Shirota, Hidenori Ojima, Nobuyoshi Hiraoka, Kazuaki Shimada, Hirofumi Rokutan, Yasuhito Arai, Yae Kanai, Shinichi Miyagawa, Tatsuhiro Shibata

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

Abstract

Cholangiocarcinoma is an aggressive malignancy with a poor prognosis, with no effective therapy other than surgical resection. Heat shock protein 90 (HSP90) is a key component of a multichaperone complex involved in the posttranslational folding of a number of client proteins, many of which play essential roles in tumorigenesis. Here, we attempted to clarify its prognostic significance and potential utility as a therapeutic target in cholangiocarcinoma. Immunohistochemical expression of HSP90 was assessed retrospectively in 399 cholangiocarcinoma cases and 17 human cholangiocarcinoma cell lines, along with the effect of a small-molecule HSP90 inhibitor (NVP-AUY922) on cholangiocarcinoma tumor growth and angiogenesis in human cholangiocarcinoma cell lines and xenografts. The positivity of HSP90 was 44.6% in intrahepatic cholangiocarcinoma (IHCC) and 32.8% in extrahepatic cholangiocarcinoma (EHCC), respectively. HSP90 expression was significantly associated with the 5-year survival rate for IHCC (P < 0.001) and EHCC (P < 0.001). HSP90 inhibition showed potent antiproliferative activity and reduced growth-associated signaling in human cholangiocarcinoma cells in vitro. Furthermore, treatment of cholangiocarcinoma xenograft-bearing mice with NVP-AUY922 significantly inhibited growth at doses far below the maximum-tolerated dose. HSP90 overexpression is a prognostic marker for cholangiocarcinoma. HSP90-targeted therapy may be an option for a subset of cholangiocarcinoma.

Original languageEnglish
Pages (from-to)1985-1993
Number of pages9
JournalMolecular cancer therapeutics
Volume14
Issue number9
DOIs
Publication statusPublished - 2015 Sep 1
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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