A molecular cascade modulates MAP1B and confers resistance to mTOR inhibition in human glioblastoma.

Autor:	Laks DR; Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience & Human Behavior, UCLA, Los Angeles, California., Oses-Prieto JA; Department of Pharmaceutical Chemistry, UCSF, San Francisco, California., Alvarado AG; Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience & Human Behavior, UCLA, Los Angeles, California., Nakashima J; Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience & Human Behavior, UCLA, Los Angeles, California., Chand S; Department of Pharmaceutical Chemistry, UCSF, San Francisco, California., Azzam DB; Department of Neuroscience, UCLA, Los Angeles, California., Gholkar AA; Chemistry, UCLA, Los Angeles, California., Sperry J; Department of Molecular and Medical Pharmacology, UCLA., Ludwig K; Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience & Human Behavior, UCLA, Los Angeles, California., Condro MC; Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience & Human Behavior, UCLA, Los Angeles, California., Nazarian S; Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience & Human Behavior, UCLA, Los Angeles, California., Cardenas A; Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience & Human Behavior, UCLA, Los Angeles, California., Shih MYS; Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience & Human Behavior, UCLA, Los Angeles, California., Damoiseaux R; Department of Molecular and Medical Pharmacology, UCLA., France B; Department of Molecular and Medical Pharmacology, UCLA., Orozco N; Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience & Human Behavior, UCLA, Los Angeles, California., Visnyei K; Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience & Human Behavior, UCLA, Los Angeles, California., Crisman TJ; Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience & Human Behavior, UCLA, Los Angeles, California., Gao F; Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience & Human Behavior, UCLA, Los Angeles, California., Torres JZ; Chemistry, UCLA, Los Angeles, California., Coppola G; Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience & Human Behavior, UCLA, Los Angeles, California.; Department of Neurology, UCLA, Los Angeles, California., Burlingame AL; Department of Pharmaceutical Chemistry, UCSF, San Francisco, California., Kornblum HI; Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience & Human Behavior, UCLA, Los Angeles, California.; Department of Molecular and Medical Pharmacology, UCLA.; Chemistry, UCLA, Los Angeles, California.
Jazyk:	angličtina
Zdroj:	Neuro-oncology [Neuro Oncol] 2018 May 18; Vol. 20 (6), pp. 764-775.
DOI:	10.1093/neuonc/nox215
Abstrakt:	Background: Clinical trials of therapies directed against nodes of the signaling axis of phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin (mTOR) in glioblastoma (GBM) have had disappointing results. Resistance to mTOR inhibitors limits their efficacy. Methods: To determine mechanisms of resistance to chronic mTOR inhibition, we performed tandem screens on patient-derived GBM cultures. Results: An unbiased phosphoproteomic screen quantified phosphorylation changes associated with chronic exposure to the mTOR inhibitor rapamycin, and our analysis implicated a role for glycogen synthase kinase (GSK)3B attenuation in mediating resistance that was confirmed by functional studies. A targeted short hairpin RNA screen and further functional studies both in vitro and in vivo demonstrated that microtubule-associated protein (MAP)1B, previously associated predominantly with neurons, is a downstream effector of GSK3B-mediated resistance. Furthermore, we provide evidence that chronic rapamycin induces microtubule stability in a MAP1B-dependent manner in GBM cells. Additional experiments explicate a signaling pathway wherein combinatorial extracellular signal-regulated kinase (ERK)/mTOR targeting abrogates inhibitory phosphorylation of GSK3B, leads to phosphorylation of MAP1B, and confers sensitization. Conclusions: These data portray a compensatory molecular signaling network that imparts resistance to chronic mTOR inhibition in primary, human GBM cell cultures and points toward new therapeutic strategies.
Databáze:	MEDLINE
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