MEK-ERK Signaling Dictates DNA-Repair Gene MGMT Expression and Temozolomide Resistance of Stem-Like Glioblastoma Cells via the MDM2-p53 Axis

Abstract

Overcoming the resistance of glioblastoma cells against temozolomide, the first-line chemotherapeutic agent of choice for newly diagnosed glioblastoma, is a major therapeutic challenge in the management of this deadly brain tumor. The gene encoding O 6 -methylguanine DNA methyltransferase (MGMT), which removes the methyl group attached by temozolomide, is often silenced by promoter methylation in glioblastoma but is nevertheless expressed in a significant fraction of cases and is therefore regarded as one of the most clinically relevant mechanisms of resistance against temozolomide. However, to date, signaling pathways regulating MGMT in MGMT-expressing glioblastoma cells have been poorly delineated. Here in this study, we provide lines of evidence that the mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)-extracellular signal-regulated kinase (ERK)-murine double minute 2 (MDM2)-p53 pathway plays a critical role in the regulation of MGMT expression, using stem-like glioblastoma cells directly derived from patient tumor samples and maintained in the absence of serum, which not only possess stem-like properties but are also known to phenocopy the characteristics of the original tumors from which they are derived. We show that, in stem-like glioblastoma cells, MEK inhibition reduced MDM2 expression and that inhibition of either MEK or MDM2 resulted in p53 activation accompanied by p53-dependent downregulation of MGMT expression. MEK inhibition rendered otherwise resistant stem-like glioblastoma cells sensitive to temozolomide, and combination of MEK inhibitor and temozolomide treatments effectively deprived stem-like glioblastoma cells of their tumorigenic potential. Our findings suggest that targeting of the MEK-ERK-MDM2-p53 pathway in combination with temozolomide could be a novel and promising therapeutic strategy in the treatment of glioblastoma. STEM CELLS

MEK2 is a prognostic marker and potential chemo-sensitizing target for glioma patients undergoing temozolomide treatment

“…Another interesting finding of our study is that MEK2 inhibitors could be used as a sensitizing strategy for TMZ treatment. Here, the administration of trametinib (GSK1120212) and PD184352 (CI-1040), two MEK1/2 inhibitors undergoing clinical trials 41 , greatly altered the apoptotic rate of glioma cells upon TMZ treatment. Notably, these inhibitors are nonselective inhibitors to MEK1 and MEK2, and the contribution of MEK1 inhibition in improved TMZ sensitivity should be further investigated in future studies.…”

Effects of Gas1 on gliomas: a review on current preclinical studies

“…Alternatively the activation of ERK is involved with the maintenance of the expression of MGMT and resistance to TMZ of GBM-GICs. [32] As previously mentioned GAS1 inhibits the activation of ERK1/2, thus it may promote the elimination of the GIC´s population [ Figure 2]. It is relevant that the overexpression of GAS1 in human adenocarcinoma cells (A549) increases their sensibility to cisplatin, which inhibits proliferation and induces cell cycle arrest and apoptosis.…”

“…[26,28,30] It is noteworthy that CD133 + GICs are predisposed to become resistant to chemo-and radiotherapy with respect to non-GICs cells, implicating the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2). [20,31,32] In this context, the use of classical therapies against gliomas, facilitate the selection of multi-resistant GICs, leading to the formation of more aggressive tumors, resistant to chemo-and radiotherapy. [33] Moreover, in vitro and in vivo studies have shown that with the adequate stimulus, GICs differentiate to either neuronal or astrocytic cells, however many of these responses are deregulated in gliomas.…”

Targeting DNA Repair Mechanisms to Treat Glioblastoma

“…More recently, the use of a mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor has shown promise as a TMZ adjuvant by activating p53 [65]. Molecules targeting miRNAs may also be effective at p53-mediated suppression of MGMT.…”