Oncotarget

Research Papers:

Sensitivity to PRIMA-1MET is associated with decreased MGMT in human glioblastoma cells and glioblastoma stem cells irrespective of p53 status

Mariia Patyka, Zeinab Sharifi, Kevin Petrecca, Jose Mansure, Bertrand Jean-Claude and Siham Sabri _

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Oncotarget. 2016; 7:60245-60269. https://doi.org/10.18632/oncotarget.11197

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Abstract

Mariia Patyka1, Zeinab Sharifi1, Kevin Petrecca2, Jose Mansure3, Bertrand Jean-Claude4, Siham Sabri5

1Division of Experimental Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, Canada

2Department of Neurology and Neurosurgery, McGill University, The Montreal Neurological Institute and Hospital, Montreal, Quebec, Canada

3Department of Urologic Oncology Research, McGill University Health Centre, Montreal, Quebec, Canada

4Department of Medicine, Division of Experimental Medicine, McGill University, The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada

5Department of Oncology, Division of Radiation Oncology, McGill University, Cancer Research Program, The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada

Correspondence to:

Siham Sabri, email: siham.sabri@mcgill.ca

Keywords: glioblastoma, p53 mutation, MGMT, PRIMA-1MET/ APR-246, glioblastoma stem cells

Received: December 16, 2015    Accepted: July 18, 2016    Published: August 11, 2016

ABSTRACT

Alterations of the TP53 tumor suppressor gene occur in ~30% of primary glioblastoma (GBM) with a high frequency of missense mutations associated with the acquisition of oncogenic “gain-of-function” (GOF) mutant (mut)p53 activities. PRIMA-1MET/APR-246, emerged as a promising compound to rescue wild-type (wt)p53 function in different cancer types. Previous studies suggested the role of wtp53 in the negative regulation of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT), a major determinant in resistance to therapy in GBM treatment. The potential role of MGMT in expression of p53 and the efficacy of PRIMA-1MET with respect to TP53 status and expression of MGMT in GBM remain unknown. We investigated response to PRIMA-1MET of wtp53/MGMT-negative (U87MG, A172), mutp53/MGMT-positive U138, LN-18, T98/Empty vector (T98/EV) and its isogenic MGMT/shRNA gene knockdown counterpart (T98/shRNA). We show that MGMT silencing decreased expression of mutp53/GOF in T98/shRNA. PRIMA-1MET further cleared T98/shRNA cells of mutp53, decreased proliferation and clonogenic potential, abrogated the G2 checkpoint control, increased susceptibility to apoptotic cell death, expression of GADD45A and sustained expression of phosphorylated Erk1/2. PRIMA-1MET increased expression of p21 protein in U87MG and A172 and promoted senescence in U87MG cell line. Importantly, PRIMA-1MET decreased relative cell numbers, disrupted the structure of neurospheres of patient-derived GBM stem cells (GSCs) and enabled activation of wtp53 with decreased expression of MGMT in MGMT-positive GSCs or decreased expression of mutp53. Our findings highlight the cell-context dependent effects of PRIMA-1MET irrespective of p53 status and suggest the role of MGMT as a potential molecular target of PRIMA-1MET in MGMT-positive GSCs.


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