Long-term In Vitro Treatment of Human Glioblastoma Cells with Temozolomide Increases Resistance In Vivo through Up-regulation of GLUT Transporter and Aldo-Keto Reductase Enzyme AKR1C Expression

Abstract

Glioblastoma (GBM) is the most frequent malignant glioma. Treatment of GBM patients is multimodal with maximum surgical resection, followed by concurrent radiation and chemotherapy with the alkylating drug temozolomide (TMZ). The present study aims to identify genes implicated in the acquired resistance of two human GBM cells of astrocytic origin, T98G and U373, to TMZ. Resistance to TMZ was induced by culturing these cells in vitro for months with incremental TMZ concentrations up to 1 mM. Only partial resistance to TMZ has been achieved and was demonstrated in vivo in immunocompromised mice bearing orthotopic U373 and T98G xenografts. Our data show that long-term treatment of human astroglioma cells with TMZ induces increased expression of facilitative glucose transporter/solute carrier GLUT/SLC2A family members, mainly GLUT-3, and of the AKR1C family of proteins. The latter proteins are phase 1 drug-metabolizing enzymes involved in the maintenance of steroid homeostasis, prostaglandin metabolism, and metabolic activation of polycyclic aromatic hydrocarbons. GLUT-3 has been previously suggested to exert roles in GBM neovascularization processes, and TMZ was found to exert antiangiogenic effects in experimental gliomas. AKR1C1 was previously shown to be associated with oncogenic potential, with proproliferative effects similar to AKR1C3 in the latter case. Both AKR1C1 and AKR1C2 proteins are involved in cancer pro-proliferative cell chemoresistance. Selective targeting of GLUT-3 in GBM and/or AKR1C proteins (by means of jasmonates, for example) could thus delay the acquisition of resistance to TMZ of astroglioma cells in the context of prolonged treatment with this drug.

Differential expression of miR200a-3p and miR21 in grade II–III and grade IV gliomas

“…[4][5][6] Consistent with this observation, we show that a few number of GBM primary cultures display growth inhibition in response to TMZ. Likewise, among 6 GBM-derived cell lines examined, 3 are shown to be TMZ-responsive.…”

“…Indeed, GBMs can present innate resistance or develop acquired resistance during TMZ treatment. [4][5][6] Resistance of GBMs to TMZ is reported to be mainly, but not exclusively, dependent on high levels of the DNA repair enzyme, O 6 -methylguanine methyltransferase (MGMT), which can reverse the methylation damage induced by alkylating agents. [7][8][9] Although a number of studies have shown that a deficiency of MGMT can augment the sensitivity of GBMs to alkylating agents such as TMZ, a panel of tumors with low levels of MGMT are nevertheless chemoresistant.…”

GLUT3 upregulation promotes metabolic reprogramming associated with antiangiogenic therapy resistance

“…While cancer cells express all 4 of these GLUTs, GLUT3 may be the predominant one in cancers such as glioblastoma (22), where it has been associated with aggressive aspects of cancer such as the epithelial to mesenchymal transition (23) and the tumor-initiating stem cells of glioblastoma (24). Interestingly, GLUT3 overexpression has also been described in temozolomide-resistant glioblastoma cell lines established in culture (25). Further work will also be needed to define whether the glycosylated versus nonglycosylated forms of GLUT3, both of which were detected in our study, serve different functional roles in the context of resistance to antiangiogenic therapy, as has been suggested for GLUT1 for some tumor cells in the absence of therapeutic stressors (26).…”

AKR1C1 as a Biomarker for Differentiating the Biological Effects of Combustible from Non-Combustible Tobacco Products

“…If o-quinones and the ROS they generate are not eliminated, they can potentially cause covalent and oxidative DNA lesions, increasing the mutational load of PAH-exposed cells. Together, this sequence of events may contribute to PAH-induced oral carcinogenesis and other malignancies [15,23,25,[53][54][55]58,59,62].…”

“…They are monomeric intracellular enzymes that catalyze the conversion of aldehydes and ketones to their corresponding alcohols by utilizing NADH and/or NADPH as cofactors, and bind bile acid with high affinity. Their enzymatic activities play crucial roles in balancing malignant transformation, cancer progression, and response to cytotoxic therapies [25,[52][53][54][55].…”