Abstract 4143: Mastl, a novel therapeutic target in colon cancer

Abstract

Abstract Combining chemoradiation with agents that modulate tumor-specific pathways such as cell cycle checkpoints has shown immense promise in preclinical and clinical studies. To ensure that only healthy cells proliferate, checkpoints have evolved that induce cell-cycle arrest in response to the detection of defects that may have arisen during DNA replication or other steps leading to mitosis. The G2/M checkpoint Mastl in mammals (and Greatwall in Xenopus and Drosophila) prevents cells from premature entry into mitosis, and thus minimizes chromosome mis-segregation. Our preliminary data demonstrate that Mastl not only plays a key role in regulating cell cycle and mitosis but also regulates key oncogenic signaling pathways and assists therapy resistance in cancer cells. Interestingly, genetic elimination of Mastl expression in vivo compromised survival in young mice, however, only mild alterations were found when deleted in adult mice. Here we show using two clinical and genomic databases using a total of 265 patient samples that Mastl expression increases in colon cancer across all cancer stages compared with the normal colon tissue (P < 0.001). Moreover, high Mastl expression associates with high-risk colorectal cancer patients and poor prognosis. Silencing of Mastl expression using gene-specific shRNA, in two different colon cancer cells with high endogenous expression of Mastl, induced cell death/apoptosis supporting important role of Mastl in colon cancer cell survival. To further determine molecular mechanism/s by which Mastl regulates cell survival, we screened a panel of oncogenes. It was interesting that the knock-down of Mastl expression sharply inhibited β-catenin/c-myc signaling, key regulators of colon carcinogenesis, in both cell types. To further expand the breadth of this investigation and to identify additional key players in Mastl dependent regulation of colon cancer cell survival, we performed an oncogenic array analysis using above cell lines with or without stable inhibition of Mastl expression. Here, we observed robust effects of inhibiting Mastl upon anti-apoptotic proteins Bcl-xl and survivin. Notably, c-myc regulates survivin and Bcl-xl expressions. Additional studies, where colon cancer cells were subjected to 5-FU treatment sharply induced Mastl expression and combinational therapy using 5FU and (targeting) Mastl resulted in significantly increased death among these cells (P>0.0025; versus control). Taken together, we here report a novel and previously undescribed role of Mastl in colon cancer progression, malignancy and therapy resistance potentially by regulating cell survival in manners dependent on β-catenin/c-Myc/Survivin/Bcl-xl signaling. Citation Format: JayaPrakash Uppada, SaiPrasad Gowrikumar, Rizwan Ahmad, Steven Chen, J Joshua Smith, Amar B. Singh, Punita Dhawan. Mastl, a novel therapeutic target in colon cancer [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 4143. doi:10.1158/1538-7445.AM2017-4143