17-AAG and sihsp90α combinational therapy as a novel anti-cancer approach
type: CreativeWork
description: Heat Shock Protein 90 (Hsp90) is a molecular chaperone which plays an active role in maintaining protein homeostasis. Hsp90 is known to be highly expressed in tumour cells where it regulates stability and function of several key oncogenic client proteins including Akt kinase, EGFR, CDK and PDGFR. These client proteins are mutated or overexpressed in tumours and are involved in tumour progression and metastasis due to their roles in signalling pathways, cell cycle and apoptosis. Hsp90 has two isoforms, namely Hsp90α and Hsp90β and share 85% sequence homology. Hsp90β is the constitutive isoform, however, Hsp90α is highly induced in many cancers and is responsible for tumourigenesis. Previous studies from our laboratory established Hsp90α mRNA and protein to be highly expressed in glioma cell lines and tissues compared to normal tissue and cells. In a follow up study, Hsp90α was silenced using predesigned small interfering RNA (sihsp90α) with high target specificity and it showed a clinical impact on the chemosensitivity to Temozolomide (TMZ). Thus, Hsp90α could be a therapeutic target for the treatment of glioma. This study utilized a Hsp90-inhibitor 17-AAG and hsp90α-specific siRNA (sihsp90α), either as single agent or in combination, to inhibit Hsp90 function in glioblastoma. Hsp90α mRNA and protein expression levels post treatment were evaluated using qRT-PCR and confocal microscopy. To determine if Hsp90α inhibition influenced Akt kinase activity, a Hsp90 client protein, Akt activity was examined in treated and control cells using a Akt Kinase activity kit. Novel results from the study revealed that Hsp90α was significantly down-regulated at both the mRNA and protein levels which were associated with reduced cell viability. Hsp90α inhibition resulted in loss of Akt kinase activity which validated the role of Hsp90α in chaperoning tumour progression. The use of 17-AAG concomitant with sihsp90α did not demonstrate synergistic anti-tumour effects in glioblastoma in v…
abstract: Heat Shock Protein 90 (Hsp90) is a molecular chaperone which plays an active role in maintaining protein homeostasis. Hsp90 is known to be highly expressed in tumour cells where it regulates stability and function of several key oncogenic client proteins including Akt kinase, EGFR, CDK and PDGFR. These client proteins are mutated or overexpressed in tumours and are involved in tumour progression and metastasis due to their roles in signalling pathways, cell cycle and apoptosis. Hsp90 has two isoforms, namely Hsp90α and Hsp90β and share 85% sequence homology. Hsp90β is the constitutive isoform, however, Hsp90α is highly induced in many cancers and is responsible for tumourigenesis. Previous studies from our laboratory established Hsp90α mRNA and protein to be highly expressed in glioma cell lines and tissues compared to normal tissue and cells. In a follow up study, Hsp90α was silenced using predesigned small interfering RNA (sihsp90α) with high target specificity and it showed a clinical impact on the chemosensitivity to Temozolomide (TMZ). Thus, Hsp90α could be a therapeutic target for the treatment of glioma. This study utilized a Hsp90-inhibitor 17-AAG and hsp90α-specific siRNA (sihsp90α), either as single agent or in combination, to inhibit Hsp90 function in glioblastoma. Hsp90α mRNA and protein expression levels post treatment were evaluated using qRT-PCR and confocal microscopy. To determine if Hsp90α inhibition influenced Akt kinase activity, a Hsp90 client protein, Akt activity was examined in treated and control cells using a Akt Kinase activity kit. Novel results from the study revealed that Hsp90α was significantly down-regulated at both the mRNA and protein levels which were associated with reduced cell viability. Hsp90α inhibition resulted in loss of Akt kinase activity which validated the role of Hsp90α in chaperoning tumour progression. The use of 17-AAG concomitant with sihsp90α did not demonstrate synergistic anti-tumour effects in glioblastoma in v…
author: Mehta, Adi Behram
language: en
keywords: A990 - Medicine & dentistry not elsewhere classified
date published: 2012-09
date modified: 2026-07-24T01:35:42Z
provider: University of Central Lancashire
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Central Lancashire