%0 Journal Article
%T Could Upregulated Hsp70 Protein Compensate for the Hsp90-Silence-Induced Cell Death in Glioma Cells?
%A Chinmay Munje
%A Leroy Shervington
%A Zarine Khan
%A Amal Shervington
%J International Journal of Brain Science
%D 2014
%R 10.1155/2014/652643
%X The molecular chaperone heat shock protein 90 alpha (Hsp90¦Á) 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 hsp90¦Á (shhsp90¦Á) 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. 1. Introduction Heat shock protein Hsp90 is upregulated in several tumours including glioma, and thus targeting its function may provide new therapeutic aspects [1, 2]. Hsp90 is a highly conserved molecular chaperone present in eukaryotic cytosol. 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 Hsp90 chaperoning contributes towards drug resistance [4], metastasis [5], and cell survival [6]. The synthesis of several natural and chemical inhibitors along with RNA inhibition using siRNA or shRNA to silence Hsp90 has been undertaken. Previous studies in our laboratory have shown that enhanced chemosensitivity is attained upon transcription inhibition of the inducible Hsp90 subunit hsp90¦Á by siRNA, suggesting that inhibiting hsp90¦Á expression by shRNA could possibly be a favourable therapeutic approach compared to conventional chemotherapies as it is target specific and has reduced toxicity. Furthermore, a combination treatment of siRNA followed by Temozolomide (TMZ) (200¨C400£¿¦ÌM) after 48 hours was significantly more effective, suggesting
%U http://www.hindawi.com/journals/ijbs/2014/652643/