MAP3K8 and cancer: Methotrexate has been proposed to act by inhibiting folate-dependent purine and pyrimidine nucleotide production, by inducing adenosine release into the extracellular space, by decreasing formation of methyl donors, and/or by increasing apoptosis via mitogen-activated protein kinase 8 (MAPK8) and MAPK9 in rheumatoid arthritis and cancer cells (30, 39–45).