Weifeng Wan1,2, Wenfeng Xiao1,3, Wen Pan1,4, Ligang Chen2, Zhiyong Liu1, Jianguo Xu5. 1. Department of Neurosurgery, West China Hospital, Sichuan University, Guoxue Street 37, Chengdu, 610041, Sichuan, People's Republic of China. 2. Department of Neurosurgery, Southwest Medical University, Luzhou, Sichuan, People's Republic of China. 3. Department of Neurosurgery, Sichuan Mianyang 404 Hospital, Mianyang, Sichuan, People's Republic of China. 4. Department of Brain, Shougang Shuigang General Hospital, Liupanshui,, Guizhou, People's Republic of China. 5. Department of Neurosurgery, West China Hospital, Sichuan University, Guoxue Street 37, Chengdu, 610041, Sichuan, People's Republic of China. xujg@scu.edu.cn.
Abstract
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.
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.
Authors: Nagore I Marín-Ramos; Moisés Balabasquer; Francisco J Ortega-Nogales; Iván R Torrecillas; Ana Gil-Ordóñez; Beatriz Marcos-Ramiro; Pedro Aguilar-Garrido; Ian Cushman; Antonio Romero; Francisco J Medrano; Consuelo Gajate; Faustino Mollinedo; Mark R Philips; Mercedes Campillo; Miguel Gallardo; Mar Martín-Fontecha; María L López-Rodríguez; Silvia Ortega-Gutiérrez Journal: J Med Chem Date: 2019-06-19 Impact factor: 7.446
Authors: Emilie Le Rhun; Matthias Preusser; Patrick Roth; David A Reardon; Martin van den Bent; Patrick Wen; Guido Reifenberger; Michael Weller Journal: Cancer Treat Rev Date: 2019-09-11 Impact factor: 12.111