Combining chemoradiation with agents that modulate tumor-specific pathways such as cell cycle checkpoints has shown immense promise in preclinical and clinical studies. The optimal application of these strategies will likely require consideration of molecular heterogeneity between patients and within individual tumors. 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. Cell cycle arrest permits repair of these defects so that an intact genome can be passed on to each daughter cell. Another important function of cell-cycle checkpoints is to effectively trigger processes (e.g., apoptosis, mitotic catastrophe, and senescence) to prevent the propagation of severely damaged or high- risk cells. Loss of normal cell-cycle control is a hallmark of human cancer. Mastl in mammals, and Greatwall in Xenopus and Drosophila, has been shown to be important for mitosis. The G2/M checkpoint such as Mastl prevents cells from premature entry into mitosis, and thus it minimizes chromosome mis-segregation. Our preliminary data demonstrate that Mastl not only plays a role in regulating cell cycle and mitosis, but also regulates a number of key oncogenic signaling pathways and regulate therapy resistance in cancer cells. Mastl upregulation have recently been shown in breast and head and neck cancer and correlates with aggressive clinicopathological features [11]. Interestingly, elimination of Mastl in vivo in young mice compromised survival, due to massive proliferation defects [12]. However, only mild alterations were found when we deleted Mastl in adult mice, predicting low toxicity in potential Mastl-based therapies to normal cells. Further, the role of Mastl in tumor resistance using cell lines derived from the initial and recurrent tumors of the same head and neck squamous cell carcinoma patients has also been demonstrated. To test our hypothesis, we proposed following studies.
Specific Aim 1 : To determine Mastl as a target for combinational anti-colon cancer therapy. Here we will perform immunostaining for Mastl protein in colon cancer patients to associate with cancer progression and therapy resistance and determine effect of Mastl inhibition in combination with 5FU-treatment in vivo in mouse models of colorectal cancer.
Specific Aim 2 : To elucidate molecular mechanism by which Mastl regulates colon cancer progression and resistance to therapy. Here we will determine a causal role of ?-catenin signaling in Mastl dependent colon cancer cell phenotype and how Mastl regulates ?-catenin.
In this grant proposal, we will determine the role of Mastl, a cell cyle checkpoint protein, in combination therapy with 5FU in vivo and also understand the molecular mechanism of its regulation in colon cancer progression.
| Uppada, Srijayaprakash Babu; Gowrikumar, Saiprasad; Ahmad, Rizwan et al. (2018) MASTL induces Colon Cancer progression and Chemoresistance by promoting Wnt/?-catenin signaling. Mol Cancer 17:111 |
