The impact of Bcl-3 expression and signaling in cancer

Abstract: Bcl-3 is a proto-oncogene and belongs to the inhibitor of ?B (I?B) family and is known to be upregulated in numerous cancers. Bcl-3 can initiate transcription of different genes involved in cell survival and cell growth. Cell proliferation is achieved through binding of Bcl-3 to cyclin D1 promoter and facilitates the rapid transition from G1 to S phase. The aim of this thesis was to investigate the role of Bcl-3 in different types of cancers including prostate, colon, and melanoma as well as to identify a selective inhibitor against Bcl-3 protein. In prostate cancer (PC) we observed the upregulation of Bcl-3 in cancer cells adjacent to infiltration of inflammatory cells. More precisely in PC cell lines we found out that Bcl-3 was upregulated with the stimulation of IL-6 through STAT3 signaling pathway. Silencing of Bcl-3 in PC cell lines sensitize these cells against anticancer drugs treatment and formed small tumors in vivo compared to control treated cells. In colon cancer we found that Bcl-3 localization differed comparing non-cancerous with cancer cells. Bcl-3 was mainly localized in cytoplasm of cancer tissue compared to nucleus in normal colon tissue. Out of six colon cancer lines three of them showed highest expression of Bcl-3. Cell fractionation analysis of these cell lines reiterated that majority of Bcl-3 protein was localized in the cytoplasm. Furthermore, the cytoplasmic localization of Bcl-3 in cancer cells correlated positively with proliferation marker Ki67 but not with the apoptotic marker cleaved caspase 3. Results obtained from this study suggest that cytoplasmic presence of Bcl-3 could be used as a diagnostic marker in certain stages of colon cancer. Since so far no inhibitors against Bcl-3 exist, we decided to identify a specific inhibitor against Bcl-3 protein. For this purpose we screened among 1368 synthetic compounds and could identify a specific Bcl-3 inhibitor. Treatment of melanoma cells with Bcl-3 inhibitor or its related derivate reduced the proliferation and arrested cells at G1/S phase of the cell cycle. Results from this study suggest that our newly identified Bcl-3 inhibitor can be used as anticancer drug to reduce the proliferation in melanoma.