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 journalArticle

12 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

Fingerprint

HSP90 Heat-Shock Proteins
Cholangiocarcinoma
Therapeutics
Heterografts
Growth
Small Heat-Shock Proteins
Cell Line
Maximum Tolerated Dose

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Shirota, T., Ojima, H., Hiraoka, N., Shimada, K., Rokutan, H., Arai, Y., ... Shibata, T. (2015). Heat shock protein 90 is a potential therapeutic target in cholangiocarcinoma. Molecular Cancer Therapeutics, 14(9), 1985-1993. https://doi.org/10.1158/1535-7163.MCT-15-0069

Heat shock protein 90 is a potential therapeutic target in cholangiocarcinoma. / Shirota, Tomoki; Ojima, Hidenori; Hiraoka, Nobuyoshi; Shimada, Kazuaki; Rokutan, Hirofumi; Arai, Yasuhito; Kanai, Yae; Miyagawa, Shinichi; Shibata, Tatsuhiro.

In: Molecular Cancer Therapeutics, Vol. 14, No. 9, 01.09.2015, p. 1985-1993.

Research output: Contribution to journalArticle

Shirota, T, Ojima, H, Hiraoka, N, Shimada, K, Rokutan, H, Arai, Y, Kanai, Y, Miyagawa, S & Shibata, T 2015, 'Heat shock protein 90 is a potential therapeutic target in cholangiocarcinoma', Molecular Cancer Therapeutics, vol. 14, no. 9, pp. 1985-1993. https://doi.org/10.1158/1535-7163.MCT-15-0069
Shirota, Tomoki ; Ojima, Hidenori ; Hiraoka, Nobuyoshi ; Shimada, Kazuaki ; Rokutan, Hirofumi ; Arai, Yasuhito ; Kanai, Yae ; Miyagawa, Shinichi ; Shibata, Tatsuhiro. / Heat shock protein 90 is a potential therapeutic target in cholangiocarcinoma. In: Molecular Cancer Therapeutics. 2015 ; Vol. 14, No. 9. pp. 1985-1993.
@article{11ac76ea03bb4a8884031134ab4f36b4,
title = "Heat shock protein 90 is a potential therapeutic target in cholangiocarcinoma",
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.",
author = "Tomoki Shirota and Hidenori Ojima and Nobuyoshi Hiraoka and Kazuaki Shimada and Hirofumi Rokutan and Yasuhito Arai and Yae Kanai and Shinichi Miyagawa and Tatsuhiro Shibata",
year = "2015",
month = "9",
day = "1",
doi = "10.1158/1535-7163.MCT-15-0069",
language = "English",
volume = "14",
pages = "1985--1993",
journal = "Molecular Cancer Therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
number = "9",

}

TY - JOUR

T1 - Heat shock protein 90 is a potential therapeutic target in cholangiocarcinoma

AU - Shirota, Tomoki

AU - Ojima, Hidenori

AU - Hiraoka, Nobuyoshi

AU - Shimada, Kazuaki

AU - Rokutan, Hirofumi

AU - Arai, Yasuhito

AU - Kanai, Yae

AU - Miyagawa, Shinichi

AU - Shibata, Tatsuhiro

PY - 2015/9/1

Y1 - 2015/9/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84941699706&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84941699706&partnerID=8YFLogxK

U2 - 10.1158/1535-7163.MCT-15-0069

DO - 10.1158/1535-7163.MCT-15-0069

M3 - Article

C2 - 26141945

AN - SCOPUS:84941699706

VL - 14

SP - 1985

EP - 1993

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

IS - 9

ER -