Mechanism and Regulation of Baxdelta2 in Colorectal Cancer



 DESCRIPTION (provided by applicant): Expression of the pro-apoptotic tumor suppressor Bax can be silenced by frameshift mutations in its microsatellite coding region, leading to a Bax-negative phenotype. Such Bax mutations occur in ~50% of hereditary nonpolyposis colorectal cancer (HNPCC) due to deficiency of mismatch repair system associated microsatellite instability (MSI). Loss of Bax has been demonstrated to increase chemoresistance and is associated with poor prognosis. Recently, we found that some "Bax-negative" tumor cells actually contain a functional Bax isoform, BaxΔ2, which is generated when alternative splicing corrects the mutation-induced frameshift. Therefore, BaxΔ2 only exists in microsatellite-mutated cells. We have demonstrated that this "salvaged" Bax∆2 is pro-death, similar to prototype Bax, but induce cell death potential through a non- mitochondrial death pathway. Importantly, colon cancer cells expressing Bax∆2 are more sensitive to selected chemotherapeutics. Therefore, we hypothesize that BaxΔ2 determines tumor malignant potential and chemotherapeutic selectivity in "Bax-negative" MSI colorectal cancer cells through a non-canonical Bax- death pathway. We have two specific aims: 1) to study the mechanism underlying Bax∆2-mediated cell death; and 2) to identify key regulators responsible for controlling Bax∆2 expression levels in MSI colorectal tumor cells. Since there was no awareness of the existence of a Bax isoform in the "Bax-negative" cancer prior to this study, we think the studies proposed in this grant application are conceptually innovative and significant because they will change the current paradigm for understanding the development and prognosis of the "Bax-negative" MSI colorectal cancer and facilitating selection of specific chemotherapeutics for this subgroup of "Bax-negative" colon cancer patients. The Illinois Institute of Technology (IIT) is a private university with a wide range of academic disciplines. The University encourages biological research and promotes integrative biomedical research with potential translational impact. IIT currently lacks several biomedical facilities, such as high-level genomic and imaging facilities, a full-featured animal facility, and clinical resources. However, IIT does have a large body of undergraduate and graduate students eager to participate in biomedical research. The PI has a strong academic credential for both education and research. The proposed project is carefully designed to exploit the strengths of IIT's research environment and maximize opportunities for student hands-on research experiences. Successful completion of the proposed studies will have a substantial positive impact on IIT's biomedical research capacity.