• Oncotarget · Sep 2016

    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.
    • Division of Experimental Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
    • Oncotarget. 2016 Sep 13; 7 (37): 60245-60269.

    AbstractAlterations 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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