Sensitivity to PRIMA-1MET is associated with decreased MGMT in human glioblastoma cells and glioblastoma stem cells irrespective of p53 status
Bibliographic record
Abstract
// Mariia Patyka 1 , Zeinab Sharifi 1 , Kevin Petrecca 2 , Jose Mansure 3 , Bertrand Jean-Claude 4 , Siham Sabri 5 1 Division of Experimental Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, Canada 2 Department of Neurology and Neurosurgery, McGill University, The Montreal Neurological Institute and Hospital, Montreal, Quebec, Canada 3 Department of Urologic Oncology Research, McGill University Health Centre, Montreal, Quebec, Canada 4 Department of Medicine, Division of Experimental Medicine, McGill University, The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada 5 Department 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-1 MET / 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-1 MET /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-1 MET with respect to TP53 status and expression of MGMT in GBM remain unknown. We investigated response to PRIMA-1 MET 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-1 MET further cleared T98/shRNA cells of mutp53, decreased proliferation and clonogenic potential, abrogated the G 2 checkpoint control, increased susceptibility to apoptotic cell death, expression of GADD45A and sustained expression of phosphorylated Erk1/2. PRIMA-1 MET increased expression of p21 protein in U87MG and A172 and promoted senescence in U87MG cell line. Importantly, PRIMA-1 MET 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-1 MET irrespective of p53 status and suggest the role of MGMT as a potential molecular target of PRIMA-1 MET in MGMT-positive GSCs.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".