Elucidation of the sulfur oxidation pathway in colorectal cancer cells and study of sulfur metabolism alterations in cancer tumorigenesis
Globally, colorectal cancer (CRC) is the third leading cause of cancer-related death and the incidence is still increasing. Our gastrointestinal tract is home to hundreds of bacterial species, constituting the gut microbiome. Hydrogen sulfide (H2S) and persulfides have been shown to affect signaling pathways and metabolic functions involved in carcinogenesis. H2S is produced in mammalian cells through the transsulfuration pathway, but intestinal cells are also exposed to H2S produced by commensal gut bacteria. The sulfur oxidation pathway plays a key role in the catabolism of H2S in mammalian cells and notably in the intestinal epithelium, but the sequence of reactions involved in this pathway remains poorly understood. The first objective of my project is to clarify the role of enzymes previously associated with H2S oxidation (SQRDL, ETHE1, TST and TSTD1) utilizing HCT116 cell lines in which these enzymes have been knocked out using the Crispr/Cas9 technology. The second objective is to investigate alterations in the sulfur oxidation pathway and disturbance of H2S homeostasis in CRC tumorigenesis and progression using the AOM-DSS mouse model. To address both of these objectives, I have successfully developed a sensitive and quantitative LC-MS/MS-based method for analyzing thiol- and persulfide-containing metabolites in cell and tissue extracts.