Abstract 2358: Impact of MDM2 inhibition on cell cycle regulation through Aurora Kinase B - CDK1 axis in prostate cancer cells

Abstract

Cyclin-dependent kinases (CDKs) are critical regulators of cell cycle progression and therefore overexpression of CDKs contributes to the proliferation of cancer cells. A variety of genetic and epigenetic events cause over activity of the CDKs in human cancers, and their inhibition can lead to cell cycle arrest and apoptosis. In malignant cells, both elevated expression of CDKs and their modulators including cyclins, and loss of expression of CDK inhibitors result in deregulated CDK activity, providing a selective growth advantage for cancer progression. In this respect, the multifunctional mouse double minute 2 homolog (MDM2) oncoprotein has been gaining a significant amount of attention towards better understanding the cell cycle regulatory mechanisms. It is well established that MDM2 gene amplification can occur in diverse human malignancies including prostate cancer. Also, MDM2 oncoprotein has been shown to exert both p53-dependent and p53-independent roles in oncogenesis. It has been well established in several laboratories, including ours, that overexpression of MDM2, can eventually lead to the inactivation of cell cycle control and loss of apoptotic ability in many tumors. However, the mechanisms underlying the regulation of CDK1 by MDM2 in cancer cells have not been fully identified. Therefore, the main objective of our study was to understand the impact of MDM2 overexpression on CDK1 that regulates cell cycle progression and apoptosis. Our preliminary data from human cell cycle PCR array experiments revealed the expression profile of genes that are involved in different phases of cell cycle regulation in LNCaP-MST cells with and without nutlin-3 treatment. Our study clearly demonstrated a significant increase in the expression level of Aurora Kinase B (AURKB), CDC25C and CDK1 in MDM2 transfected LNCaP-MST cells as compared with non-transfected LNCaP cells. However, after treating the cells with 20 µM of MDM2 specific inhibitor nutlin-3, for 24 h, the expression levels of the above mentioned proteins were significantly altered when compared to untreated controls. In addition, inhibition of MDM2 with nutlin-3 leads to increased expression of pro-apoptotic proteins p53, p21, and Bax. Our results offer significant evidence towards the effectiveness of MDM2 inhibition in causing cell cycle arrest via blocking the transmission of signals through AURKB-CDK1 axis and inducing apoptosis in cancer cells. It is clearly evident from our data that MDM2 overexpression probably is the primary cause for CDK1 up-regulation in the LNCaP-MST cells, which might have occurred possibly through activation of AURKB. However, further studies in this direction should shed more light on the intracellular mechanisms involved in the regulation of CDK1 in MDM2 positive cancers. (This project was supported by The Royal Dames of Cancer Research Inc., Ft. Lauderdale, Florida).

Citation Format: Thanigaivelan Kanagasabai, Khalid Alhazzani, Thiagarajan Venkatesan, Sivanesan Dhandayuthapani, Ali Alaseem, Appu Rathinavelu. Impact of MDM2 inhibition on cell cycle regulation through Aurora Kinase B - CDK1 axis in prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2358. doi:10.1158/1538-7445.AM2017-2358