Harmine suppresses hyper-activated Ras–MAPK pathway by selectively targeting oncogenic mutated Ras/Raf in Caenorhabditis elegans

Background Mutationally activated Ras proteins are closely linked to a wide variety of human cancers. Hence, there has been an intensive search for anti-Ras therapies for cancer treatment. The sole Ras gene, which encodes LET-60, in Caenorhabditis elegans regulates vulval development. While the loss of let - 60 function leads to failure of vulva formation, the let - 60 ( n1046gf ) allele, which contains a missense mutation mimicking a Ras codon 13 mutation found in human cancers, results in extra vulval tissue, a phenotype named Muv (multiple vulvas). Methods By taking advantage of the easy-to-score Muv phenotype of let - 60 ( n1046gf ), we used a step-by-step screening approach (from crude extract to active fraction to active natural compound) to search for inhibitors of oncogenic Ras. Mutants of other key components in the Ras–mitogen-activated protein kinase (MAPK) pathway were used to identify other candidate targets. Results The natural compound harmine, isolated from the plant Peganum harmala , was found to suppress the Muv phenotype of let - 60 ( n1046gf ). In addition, harmine targets the hyper-activation of the Ras/MAPK pathway specifically caused by overexpression or mutated forms of LET-60/Ras and its immediate downstream molecule LIN-45/Raf. Finally, harmine can be absorbed into the worm body and probably functions in its native form, rather than requiring metabolic activation. Conclusion In sum, we have revealed for the first time the anti-Ras activity of harmine in a C. elegans model system. Our results revealed the potential anti-cancer mechanism of harmine, which may be useful for the treatment of specific human cancers that are associated with oncogenic Ras mutations.