Isoprenylcysteine carboxyl methyltransferase is critical for glioblastoma growth and survival by activating Ras/Raf/Mek/Erk

Purpose The poor outcomes in glioblastoma necessitate new therapeutic target. Isoprenylcysteine carboxyl methyltransferase (ICMT), a unique enzyme of the final step of prenylation that modifies activities of oncogenic proteins, represents a promising target for many cancers. Methods Expression pattern, function and downstream pathway of ICMT in glioblastoma were analyzed using immunohistochemistry, ELISA, cellular assays and immunoblotting method. Combinatory effect was analyzed using Chou-Talalay approach. Results Upregulation of ICMT expression is a common phenomenon in glioblastoma patients regardless of clinicopathological characteristics. Gain-of-function and loss-of-function analysis support the role of ICMT in glioblastoma growth and survival but not migration. Importantly, pharmacological inhibitors of ICMT are effectively against glioblastoma cells while sparing normal neuron cells, and furthermore that they act synergistically with chemotherapeutic drugs. Consistently, ICMT inhibitor UCM-1336 significantly inhibits glioblastoma growth without causing toxicity in mice. Mechanistic studies demonstrate that Ras/Raf/Mek/Erk rather than Ras/PI3K/Akt/mTOR is the downstream pathway of ICMT-mediated glioblastoma growth. Conclusions Our findings provide the proof-of-concept of pharmacologically targeting ICMT in the treatment of glioblastoma via deactivation of Ras/Raf/Mek/Erk.