Abstract
The molecular chaperone heat shock protein 90 alpha (Hsp90α) has been recognized in various tumours including glioma. This pilot study using a proteomic approach analyses the downstream effects of Hsp90 inhibition using 17-allylamino-17-demethoxygeldanamycin (17AAG) and a short hairpin RNA (shRNA) oligonucleotide targeting hsp90α (shhsp90α) in the U87-MG glioma cell line. Preliminary data coupled with bioinformatic analysis identified several known and unknown Hsp90 client proteins that demonstrated a change in their protein expression after Hsp90 inhibition, signifying an alteration in the canonical pathways of cell cycle progression, apoptosis, cell invasion, angiogenesis, and metastasis. Members of the glycolysis pathway were upregulated, demonstrating increased dependency on glycolysis for energy source by the treated glioma cells. Upregulated proteins also include Hsp70 and members of its family such as Hsp27 and gp96, thereby suggesting the role of Hsp90 co-chaperones in compensating for Hsp90 function after Hsp90 inhibition. Considering Hsp70’s role in antiapoptosis, it was postulated that a combination therapy involving a multitarget approach could be carried out. Consequently inhibition of both Hsp90 and Hsp70 in U87-MG glioma cells resulted in 60% cell death indicating the importance of combination therapy for glioma therapeutics.
Highlights
Heat shock protein Hsp90 is upregulated in several tumours including glioma, and targeting its function may provide new therapeutic aspects [1, 2]
These results demonstrate that both treatments can significantly inhibit the expression of Hsp90α in the U87-MG glioma cell line (∗∗P < 0.001)
The pilot study showed that the treatment of U87-MG glioma cells with 17AAG and short hairpin RNA (shRNA) to target hsp90α, effectively reduced Hsp90α activity and subsequently reduced the Akt/PKB kinase activity in U87-MG cell line
Summary
Heat shock protein Hsp is upregulated in several tumours including glioma, and targeting its function may provide new therapeutic aspects [1, 2]. It has been proposed to play a vital role in tumorigenesis, maintenance of transformation and regulation of several key proteins involved in apoptosis and survival and growth pathways [3]. These pathways are exploited in tumours where Hsp chaperoning contributes towards drug resistance [4], metastasis [5], and cell survival [6]. Previous studies in our laboratory have shown that enhanced chemosensitivity is attained upon transcription inhibition of the inducible Hsp subunit hsp90α by siRNA, suggesting that inhibiting hsp90α expression by shRNA could possibly be a favourable therapeutic approach compared to conventional chemotherapies as it is target specific and has reduced toxicity. This study investigated Hsp chaperone inhibition with (a) 17-allylamino-17-demethoxygeldanamycin (17AAG), an analogue of Geldanamycin (GA) and a potent Hsp inhibitor and (b) short hairpin RNA (shRNA) oligonucleotide targeted against hsp90α
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