Phosphorylation of IMPDH2 promotes lung cancer lymph node metastasis

Abstract Lymph node (LN) metastasis (LNM) represents not only the most frequent site of metastasis but also a pivotal factor that contributes to poor clinical outcomes in lung cancer patients. Unveiling the intrinsic regulatory mechanism of LNM is of paramount importance. In this study, we report that the phosphorylation of IMPDH2 promotes the lymph node metastasis of lung cancer. We revealed that IMPDH2 is highly expressed in lung cancer and that high IMPDH2 expression indicates poor survival and prognosis and high LNM potential. IMPDH2 facilitated lung cancer cell growth, migration and invasion as well as in vivo growth and LNM in an EMT-related manner. Mechanistically, GSK3β binds and phosphorylates IMPDH2 at the 440th serine residue, which stimulates the enzyme activity of IMPDH2 in the GTP synthesis pathway, further up-regulating the activity of small GTPases. The downstream products of IMPDH2, XMP (xanthosine 5’-monophosphate) and GTP, could rescue the malignant phenotypes induced by silencing of IMPDH2 and a catalytically defective IMPDH2 mutant (IMPDH2 S440A ). Mycophenolic acid (MPA), an inhibitor of IMPDH2, suppressed the malignant phenotype of lung cancer cells. In conclusion, IMPDH2 promotes lung cancer progression in a GTP synthesis-dependent manner, and IMPDH2 is a potential therapeutic target for metastatic NSCLC.