Expression and therapeutic relevance of heat-shock protein 90 in pancreatic endocrine tumors

Abstract

Pancreatic endocrine tumors (PET) represent a heterogenous group of neoplasms. Although surgical resection is considered a safe and effective treatment for many PET, therapeutic options for inoperable and progressive PET are limited. The expression of heat-shock protein (HSP) 90 was investigated in 120 clinically and pathomorphologically well-characterized PET from 84 patients using immunohistochemistry. In addition, in 19 snap-frozen PET and in three healthy pancreatic tissues, we performed immunoblot analyses, and in 15 snap-frozen PET and in three healthy pancreatic tissues, we investigated the expression of HSP90 isoforms by means of semiquantitative RT-PCR. Functional tests were conducted using the human pancreas carcinoid cell line BON and the mouse insulinoma cell line b-TC-3. HSP90 was expressed in 95% of the PET patients. The transcript levels of the HSP90 isoforms HSP90a, HSP90b, glucose-related protein 94, and TNF receptor-associated protein 1 were significantly increased in PET compared with non-neoplastic pancreatic tissues. The treatment of the cell lines BON and b-TC-3 with the HSP90 inhibitors 17-allylamino-17-demethoxygeldanamycin and 17-dimethylaminoethylamino-17-demethoxy-geldanamycin resulted in significant, dose-dependent reduction of cell viability, cell cycle arrest, and increased apoptosis. Furthermore, HSP90 inhibition induced the degradation and inactivation of several oncogenetic HSP90 client proteins in a time-and dose-dependent manner. HSP90 inhibitors increased the therapeutic effects of doxorubicin and 5-fluorucacil in BON and b-TC-3 cells. HSP90 is expressed in the vast majority of PET and its inhibition reveals significant treatment effects in vitro. Thus, HSP90 qualifies as a promising new target.

Acinar cell carcinomas of the pancreas: a molecular analysis in a series of 57 cases

“…In a previous study, we demonstrated HSP90 expression in 95 % of PNENs and provided functional evidence that HSP90 targeting shows significant therapeutic effects in vitro [59]. Thus, treatment of PNEN cell lines with HSP90 inhibitors, 17-AAG and 17 DMAG, resulted in reduction of cell viability, cell cycle arrest, and increased apoptosis [59]. Furthermore, HSP90 inhibition led to degradation and inactivation of several oncogenic client proteins and an increased therapeutic efficacy of the conventional chemotherapeutic agents 5-FU and doxorubicin [59].…”

“…In a previous study, we demonstrated HSP90 expression in 95 % of PNENs and provided functional evidence that HSP90 targeting shows significant therapeutic effects in vitro [59]. Thus, treatment of PNEN cell lines with HSP90 inhibitors, 17-AAG and 17 DMAG, resulted in reduction of cell viability, cell cycle arrest, and increased apoptosis [59].…”

“…Thus, treatment of PNEN cell lines with HSP90 inhibitors, 17-AAG and 17 DMAG, resulted in reduction of cell viability, cell cycle arrest, and increased apoptosis [59]. Furthermore, HSP90 inhibition led to degradation and inactivation of several oncogenic client proteins and an increased therapeutic efficacy of the conventional chemotherapeutic agents 5-FU and doxorubicin [59]. HSP90 expression has also been shown in various other neoplasms, including PDACs [60].…”

Inhibition of Heat Shock Protein 90 with AUY922 Represses Tumor Growth in a Transgenic Mouse Model of Islet Cell Neoplasms

“…HSP90 has been considered a promising new therapeutic target in other neoplasms, including pancreatic ductal adenocarcinoma [27], hepatocellular carcinoma [28], breast cancer [29], esophageal and gastric cancers [30], and others. With regard to pNENs, HSP90 expression has been described in almost 95% of pNENs and, therefore, might be an interesting novel target for antineoplastic therapy in pNENs [6]. The present study provides evidence that targeting HSP90 impairs activation of oncogenic signaling including Akt/mTOR activation.…”

“…Recently, Mayer et al [6] found heat shock protein 90 (HSP90) to be expressed in 95% of specimens from pNEN patients. HSP90 is a molecular chaperone that comprises 1-2% of total cellular protein content and regulates the correct folding, activity, function, and stability of over 200 client proteins [7].…”