GTP Metabolism Regulates Cancer Cell Invasion

Invasion is a prerequisite for metastasis which is the most detrimental feature of virtually all types of cancers. Tumor cell invasion has been strongly associated with the activity of small GTPases, in particular those of the RHO‐GTPase family. The question of whether tumor cells possess intrinsic ability to regulate activity of the above GTPases and subsequently invasion by manipulating intracellular GTP pools has never been addressed. We demonstrate that a purine nucleotide metabolism enzyme guanosine monophosphate reductase (GMPR) suppresses the ability of highly invasive melanoma cells to invade in vitro and grow as tumor xenografts in vivo. Mechanistically, GMPR partially depleted intracellular GTP pools and reduced the amounts of several GTP‐bound (active) RHO‐GTPases. shRNA‐mediated inhibition of GMPR or addition of exogenous guanosine increased activity of the same RHO‐GTPases and up‐regulated invasion in melanoma cells and cells from different types of cancers. Ectopic expression of constitutively active RAC1 G12V , insensitive to GTP depletion, substantially reverted GMPR‐dependent phenotypes. The functional role of intracellular GTP levels in tumor cell invasion was confirmed by inhibiting activity of other enzymes involved in the de novo guanylate biosynthesis. Our data identified a previously unrecognized ability of cancer cells to increase the activity of RHO‐GTPases via up‐regulation of GTP pools, and established a novel and fundamental connection between tumor cell invasion and metabolism of guanylates