Abstract 81: Effect of HSP90 inhibition on the gene expression profile of MDM2 transfected LNCaP-MST prostate cancer cells

Abstract

Abstract The heat shock protein 90 (HSP90) is a major molecular chaperone of the cell that appears to be a master regulator of the stability and activity of multiple oncoproteins such as HER2, Akt, Bcr-Abl, c-Kit, EGFR and BRAF. Recent approaches have revealed that most of the target proteins of HSP90 are protein kinases or transcription factors which play important roles in the cellular carcinogenesis. The HSP90 also plays an important role in the regulation of cell cycle, proliferation, vascularization, invasion and metastasis of cancer cells, as well as in maintaining the stability and functions of several carcinogenic proteins involved in altering the signal transduction pathways of apoptosis. The 17-allylamino-17-demethoxygeldanamycin (17-AAG) is a well known inhibitor of HSP90 and it was speculated that, this inhibitor may have particular value in the antitumor and angiostatic therapies. Hence, we were trying to determine the expression profile of the genes in the angiogenesis pathway following treatment of MDM2 overexpressing LNCaP-MST prostate cancer cells with 17-AAG. In the LNCaP-MST cells, the expression of genes such as TNF-α, MMP9 and TGFB1 were found to be significantly up-regulated compared to the LNCaP cells. Hence, MDM2 overexpression was suspected as the primary cause of these increases. However, after treating the LNCaP-MST cells with 10 μm 17-AAG for 24 hrs, several of these genes were significantly altered compared to the untreated LNCaP-MST cells. In particular, the 17-AAG treatment significantly down-regulated the expression of TNF-α, TGFB1, ID1, IL8 and F3 which are involved in the regulation of angiogenesis and tumor growth. The heat map and scatterplot analysis clearly confirmed the alterations in the expression levels of these genes following 17-AAG treatment. Cluster analysis further indicated that the gene expression patterns are positively correlated with the anti-angiogenic effects of 17-AAG treatment in LNCaP-MST cells compared to untreated cells. Our results offer convincing evidence to suggest that the inhibition of HSP90 can control both pro-angiogenic and cell proliferative signals in LNCaP-MST cells. (The financial support from the Royal Dames of Cancer Research Inc., Ft. Lauderdale, Florida is gratefully acknowledged). Citation Format: Thiagarajan Venkatesan, Ali Alaseem, Khalid Alhazzani, Appu Rathinavelu. Effect of HSP90 inhibition on the gene expression profile of MDM2 transfected LNCaP-MST prostate cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 81. doi:10.1158/1538-7445.AM2015-81