IL-1β pathway and Colon Cancer: relationship and therapeutic implications in novel colon cancer cell lines derived from African American patients

Abstract

Background: African Americans (AAs) present with the highest incidence and mortality rate for CRC. When compared to Caucasian Americans (CA), AAs present reduced response to the chemotherapeutic agent 5-Fluorouracil (5-FU), and an increased expression of genes encoding proteins involved in inflammatory processes. Here, we investigate the role of Interleukin-1β (IL-1β), in promoting cell survival and modifying chemotherapeutic response in novel AA colon cancer cell lines. Methods: RNA sequencing analysis was performed to detect expression of genes in AA and CA colon cancer cell lines. MTS and Western Blot assays were used to assess the effects of IL-1β in terms of cell proliferation and protein expression, respectively. We performed cell viability assay and apoptosis analysis to evaluate the effects of IL-1β on 5-FU response. Finally, we used an IL-1 Receptor antagonist (IL-1Ra) to inhibit IL-1β-induced effects on cell proliferation, 5-FU treatment and activation of inflammatory pathways. Results: AA colon cancer cell lines displayed significant increase in expression of genes related to IL-1β and NF-kB pathways. Our results showed a more pronounced increase in cell proliferation, following treatment with IL-1β, in the AA cell lines. A decrease in the response to 5-FU treatment was observed following IL-1β treatment, in both AA and CA cell lines, as well as activation of different molecular pathways among the four cell lines. IL-1Ra blocked the effects induced by IL-1β by decreasing cell proliferation, increasing sensitivity to 5-FU and inhibiting activation of NF-kB pathway. Conclusions: Our results revealed a differential expression and activation of inflammatory pathways that might regulate the variable response to IL-1β between AA and CA colon cancer cell lines. Our data also demonstrated that IL-1β is involved in modulating 5-FU response in both AA and CA colon cancer cell lines and that IL-1Ra could be used to further improve sensitivity to 5-FU therapy in presence of high levels of IL-1β. Further investigation of these mechanisms will help elucidate the differences seen in incidence, mortality, and response to therapy in AA colon cancer patients.