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 maximumtolerated dose. HSP90 overexpression is a prognostic marker for cholangiocarcinoma. HSP90-targeted therapy may be an option for a subset of cholangiocarcinoma.

Heat Shock Proteins: Agents of Cancer Development and Therapeutic Targets in Anti-Cancer Therapy

“…HSP90 family consists of five members that are encoded by the HSPC1-5 genes which modulate tumor growth, adhesion, invasion, metastasis, angiogenesis, and apoptosis [51]. Many studies have reported that HSP90 is often overexpressed and associated with poor prognosis in multiple tumors, including cholangiocarcinoma, lung, gastric, and breast cancers and glioblastoma [8,[66][67][68][69]. The increased expression of HSP90 promotes carcinogenesis through regulation of correct folding, stability, and function of numerous oncogenic proteins.…”

Establishment of various biliary tract carcinoma cell lines and xenograft models for appropriate preclinical studies

“…Some of our established cell lines were found to be resistant to gemcitabine (Table 2), thereby allowing highly practical preclinical studies to be conducted. In addition, we conducted molecular pathology analyses of cell lines and constructed a clinical pathological database of patients undergoing BTC resection to establish appropriate parameters for drug efficacy studies to explore new biomarkers for practical applications (Figure 1)[2-5]. All experiments were approved by the Animal Care and Ethics Committee of the National Cancer Center (ID: T05-046).…”

Prognostic Significance of HER-2 and p53 Expression in Gallbladder Carcinoma in North Indian Patients

“…Combining therapies that inhibit different intracellular signaling pathways have the potential to be more effective than inhibition of a single pathway and overcoming tumor resistance. A new promise in gallbladder treatment is the inhibition of the master heat shock protein 90, a protein that in the last decade has emerged as an exciting target for cancer therapy, which is a master regulator of the stability and activity of multiple oncoproteins such as p53, HER-2, Akt, Bcr-Abl, c-Kit, EGFR and mutant BRAF [24]. Thus, our study assesses the expression of two major genes involved in the pathogenesis of GBC, correlates it with clinicopathological parameters and establishes it as an independent prognostic factor in GBC.…”