Abstract
Abstract
MDM2 gene is a cellular proto-oncogene amplified in 25-40% of all human cancers and regulates cell proliferation, senescence, and apoptosis through targeting p53. It is widely speculated that MDM2 protein is not only responsible for tumorigenesis via p53 inactivation, but also for increasing the metastatic ability of originally non-metastatic tumor cells. HSP90 is a molecular chaperone that regulates the maturation, activation and stability of critical signaling proteins that drive the development and progression of prostate cancer. 17-Allyamino-17-demethoxygeldanamycin (17-AAG) is an inhibitor of HSP90, which causes proteasomal degradation of client proteins such as AR, HER2, Akt etc., leading to cell cycle arrest and substantial growth inhibition. HSP90 is also believed to be involved in the stabilization of MDM2 and therefore, inhibition of HSP90 is expected to accelerate degradation of MDM2 and disrupt its function. Hence, our study was designed to determine the expression profile of the genes in the cell cycle pathway following treatment of MDM2 overexpressing LNCaP-MST prostate cancer cells with 17-AAG (10 μM at 24 hrs). In the present study, Human cell cycle PCR array was used to examine the alterations in gene expression pattern following exposure to the 17-AAG in MDM2 overexpressed prostate cancer cells. In our experiments we observed that the genes impacted by MDM2 overexpression were reversed by HSP90 inhibition. The expression of genes such as CDC25A, CDC25C, AURKB and Survivin levels were significantly down-regulated after 17-AAG treatment, while p21 and GADD45A were up-regulated compared to the control LNCaP-MST. A heat map and scatterplot analysis clearly confirmed the alterations in the expression levels of these genes following 17-AAG treatment. It is expected that more thorough understanding of the consequences of HSP90 blockade, particularly those that are independent of its role as a regulator of p53, will reveal its therapeutic significance. Our results offer convincing evidence to suggest that the inhibition of HSP90 can induce cell cycle arrest 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, Priya Dondapati, Saad Alobid, Appu Rathinavelu. Analysis of cell cycle-related gene expressions in MDM2-transfected LNCaP-MST cells after inhibition of HSP90. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1839.