Temozolomide Induces the Acquisition of Invasive Phenotype by O6-Methylguanine-DNA Methyltransferase (MGMT)+ Glioblastoma Cells in a Snail-1/Cx43-Dependent Manner

Abstract

Glioblastoma multiforme (GBM) recurrences after temozolomide (TMZ) treatment result from the expansion of drug-resistant and potentially invasive GBM cells. This process is facilitated by O6-Methylguanine-DNA Methyltransferase (MGMT), which counteracts alkylating TMZ activity. We traced the expansion of invasive cell lineages under persistent chemotherapeutic stress in MGMTlow (U87) and MGMThigh (T98G) GBM populations to look into the mechanisms of TMZ-induced microevolution of GBM invasiveness. TMZ treatment induced short-term, pro-invasive phenotypic shifts of U87 cells, in the absence of Snail-1 activation. They were illustrated by a transient induction of their motility and followed by the hypertrophy and the signs of senescence in scarce U87 sub-populations that survived long-term TMZ stress. In turn, MGMThigh T98G cells reacted to the long-term TMZ treatment with the permanent induction of invasiveness. Ectopic Snail-1 down-regulation attenuated this effect, whereas its up-regulation augmented T98G invasiveness. MGMTlow and MGMThigh cells both reacted to the long-term TMZ stress with the induction of Cx43 expression. However, only in MGMThigh T98G populations, Cx43 was directly involved in the induction of invasiveness, as manifested by the induction of T98G invasiveness after ectopic Cx43 up-regulation and by the opposite effect after Cx43 down-regulation. Collectively, Snail-1/Cx43-dependent signaling participates in the long-term TMZ-induced microevolution of the invasive GBM front. High MGMT activity remains a prerequisite for this process, even though MGMT-related GBM chemoresistance is not necessary for its initiation.

In Vitro Validation of the Therapeutic Potential of Dendrimer-Based Nanoformulations against Tumor Stem Cells

“…Despite numerous studies that have appointed Lyn as a key molecule of tumorigenesis, specific inhibitors for this kinase are still lacking. Several inhibitors can potently block the kinase activity of Lyn as part of a pan-SFK inhibition through their interaction with the catalytic domain, but all have wide spectra of additional targets, most likely due to the homolog of the fold of the kinase domain, which is similar to all other known protein kinases [ 3 , 4 ]. This can partially explain the limited efficacy of dasatinib in some tumor entities including glioblastoma, despite its high potency to induce tumor cell death [ 5 , 6 ].…”

The Bi-(AID-1-T) G-Quadruplex Has a Janus Effect on Primary and Recurrent Gliomas: Anti-Proliferation and Pro-Migration

“…Surprisingly, glioma cells surviving after therapy escape from the tumor to the parenchyma of a healthy human brain like living beings. It seems that the more intense and effective the therapy is, the higher the ability of surviving cells to migrate [ 16 , 17 , 18 ]. For example, Shimizu et al showed that bevacizumab therapy kills many tumor cells, but surviving cells have upregulation of δ-catenin expression, and it is associated with increased invasion of glioma cells [ 15 ].…”

“…For example, Shimizu et al showed that bevacizumab therapy kills many tumor cells, but surviving cells have upregulation of δ-catenin expression, and it is associated with increased invasion of glioma cells [ 15 ]. Another study by Kochanowski et al showed that TMZ possibly enhances the invasiveness of surviving tumor cells and that this invasiveness correlates with upregulation of ectopic expression of Snail1 [ 17 ].…”

Olea europaea Leaf Phenolics Oleuropein, Hydroxytyrosol, Tyrosol, and Rutin Induce Apoptosis and Additionally Affect Temozolomide against Glioblastoma: In Particular, Oleuropein Inhibits Spheroid Growth by Attenuating Stem-like Cell Phenotype

“…MGMT is expressed in both cell lines. However, this is much higher in T98G cells such that TMZ resistance is demonstrated, while only a low basal amount is observed in A172 [ 32 , 33 ]. In addition, in contrast to A172 cells, T98G cells express the S100 protein that functions as an intracellular Ca 2+ sensor, which contributes to tumorigenic processes and facilitates drug resistance [ 34 ].…”