Glutathione S-Transferase M3 Is Associated with Glycolysis in Intrinsic Temozolomide-Resistant Glioblastoma Multiforme Cells

Abstract

Glioblastoma multiforme (GBM) is a malignant primary brain tumor. The 5-year relative survival rate of patients with GBM remains <30% on average despite aggressive treatments, and secondary therapy fails in 90% of patients. In chemotherapeutic failure, detoxification proteins are crucial to the activity of chemotherapy drugs. Usually, glutathione S-transferase (GST) superfamily members act as detoxification enzymes by activating xenobiotic metabolites through conjugation with glutathione in healthy cells. However, some overexpressed GSTs not only increase GST activity but also trigger chemotherapy resistance and tumorigenesis-related signaling transductions. Whether GSTM3 is involved in GBM chemoresistance remains unclear. In the current study, we found that T98G, a GBM cell line with pre-existing temozolomide (TMZ) resistance, has high glycolysis and GSTM3 expression. GSTM3 knockdown in T98G decreased glycolysis ability through lactate dehydrogenase A activity reduction. Moreover, it increased TMZ toxicity and decreased invasion ability. Furthermore, we provide next-generation sequencing–based identification of significantly changed messenger RNAs of T98G cells with GSTM3 knockdown for further research. GSTM3 was downregulated in intrinsic TMZ-resistant T98G with a change in the expression levels of some essential glycolysis-related genes. Thus, GSTM3 was associated with glycolysis in chemotherapeutic resistance in T98G cells. Our findings provide new insight into the GSTM3 mechanism in recurring GBM.

Glutathione S-Transferases S1, Z1 and A1 Serve as Prognostic Factors in Glioblastoma and Promote Drug Resistance through Antioxidant Pathways

“…Prominent members of the GST family, such as GST pi 1 (GSTP1), tend to be highly expressed in various cancers. These enzymes promote tumor survival, proliferation, and drug resistance by inhibiting apoptotic pathways involving c-Jun N-terminal kinases (JNK), and autophagy pathways, such as those involving phosphoinositide 3-kinases [ 12 , 13 , 14 , 15 , 16 , 17 ].…”

Role of the mitophagy‐apoptosis axis in the pathogenesis of polycystic ovarian syndrome

“…Fetal ovaries exposed to a hyperandrogenemic environment can be reprogrammed during fetal development and have a profound effect on glucose metabolism, mitochondrial function, and mitophagy through genetic and epigenetic changes. 75,84,88 We believe that androgen excess shifts mitochondrial dynamics toward fission results in an extensive range of granulosa cell and oocyte death through loss of compensatory reserve (Figure 2). The fundamental processes for PCOS development include genetic predisposition, altered expression of genes related to glycolysis and mitochondrial function, impaired mitophagic function, and disruption of their compensatory mechanisms (see subsections 3.3 and 3.4).…”

“…127 The developmental origin of health and disease (DOHaD) hypothesis postulates that poor nutrition during embryonic and early fetal stages increases the risk of diabetes later in life, 128 which reminds us of the possibility that androgen excess can influence the mitochondrial function of offspring, leading to the development of PCOS at birth or in adulthood. [19][20][21]75,84,88,129 In conclusion, current understanding is that fetal ovaries exposed to a hyperandrogenemic environment are reprogrammed during fetal development, leading to the PCOS phenotype at birth or in adulthood possibly through genetic predisposition, aberrant expression of genes related to glycolysis and mitochondrial function, disruption of compensatory mechanisms for mitophagy, or a combination of any of these factors. In this review, a compensatory mechanism-based view is proposed for understanding the complexity of mitochondrial function and mitophagy.…”

Recent insights into the microRNA-dependent modulation of gliomas from pathogenesis to diagnosis and treatment

“…Notably, miR-379-5p exerts it effects by detoxifying microsomal glutathione transferase 1 (MGST1) [ 140 ]. High levels of glutathione transferase undesirably correlate with chemoresistance and poor survival, as these enzymes may bind to chemotherapy-induced cytotoxic agents, blocking their tumoricidal effects [ 141 , 142 ]. Consistently, lower levels of MGST1 induced by miR-379-5p are linked to the improved survival, according to a study performed by Yang et al.…”