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The glutathione S-transferase (GST) family of detoxification enzymes can regulate the malignant progression and drug resistance of various tumors. Hematopoietic prostaglandin D synthase (HPGDS, also referred to as GSTS1), GSTZ1, and GSTA1 are abnormally expressed in multiple cancers, but their roles in tumorigenesis and development remain unclear. In this study, we used bioinformatics tools to analyze the connections of HPGDS, GSTZ1, and GSTA1 to a variety of tumors in genetic databases. Then, we performed biochemical assays in GBM cell lines to investigate the involvement of HPGDS in proliferation and drug resistance. We found that HPGDS, GSTZ1, and GSTA1 are abnormally expressed in a variety of tumors and are associated with prognoses. The expression level of HPGDS was significantly positively correlated with the grade of glioma, and high levels of HPGDS predicted a poor prognosis. Inhibiting HPGDS significantly downregulated GBM proliferation and reduced resistance to temozolomide by disrupting the cellular redox balance and inhibiting the activation of JNK signaling. In conclusion, this study suggested that HPGDS, GSTZ1, and GSTA1 are related to the progression of multiple tumors, and HPGDS is expected to be a prognostic factor in GBM.

Failed neuroprotection leads to the initiation of several diseases. SOX1 plays many roles in embryogenesis, oncogenesis, and male sex determination, and can promote glioma stem cell proliferation, invasion, and migration due to its high expression in glioblastoma cells. The functional versatility of the SOX1 gene in malignancy, epilepsy, and Parkinson's disease, as well as its adverse effects on dopaminergic neurons, makes it an interesting research focus. Hence, we collate the most important discoveries relating to the neuroprotective effects of SOX1 in brain cancer and propose hypothesis worthy of SOX1's role in the survival of senescent neuronal cells, its roles in fibroblast cell proliferation, and cell fat for neuroprotection, and the discharge of electrical impulses for homeostasis. Increase in electrical impulses transmitted by senescent cells affects the synthesis of neurotransmitters, which will modify the brain cell metabolism and microenvironment.

Glioma is a type of brain and spinal cord tumor that begins in glial cells that support the nervous system neurons functions. Age, radiation exposure, and family background of glioma constitute are risk factors of glioma initiation. Gliomas are categorized on a scale of four grades according to their growth rate. Grades one and two grow slowly, while grades three and four grow faster. Glioblastoma is a grade four gliomas and the deadliest due to its aggressive nature (accelerated proliferation, invasion, and migration). As such, multiple therapeutic approaches are required to improve treatment outcomes. Recently, studies have implicated the significant roles of immune cells in tumorigenesis and the progression of glioma. The energy demands of gliomas alter their microenvironment quality, thereby inducing heterogeneity and plasticity change of stromal and immune cells via the PI3K/AKT/mTOR pathway, which ultimately results in epigenetic modifications that facilitates tumor growth. PI3K is utilized by many intracellular signaling pathways ensuring the proper functioning of the cell. The activation of PI3K/AKT/mTOR regulates the plasma membrane activities, contributing to the phosphorylation reaction necessary for transcription factors activities and oncogenes hyperactivation. The pleiotropic nature of PI3K/AKT/mTOR makes its activity unpredictable during altered cellular functions. Modification of cancer cell microenvironment affects many cell types, including immune cells that are the frontline cells involved in inflammatory cascades caused by cancer cells via high cytokines synthesis. Typically, the evasion of immunosurveillance by gliomas and their resistance to treatment has been attributed to epigenetic reprogramming of immune cells in the tumor microenvironment, which results from cancer metabolism. Hence, it is speculative that impeding cancer metabolism and/or circumventing the epigenetic alteration of immune cell functions in the tumor microenvironment might enhance treatment outcomes. Herein, from an oncological and immunological perspective, this review discusses the underlying pathomechanism of cell-cell interactions enhancing glioma initiation and metabolism activation and tumor microenvironment changes that affect epigenetic modifications in immune cells. Finally, prospects for therapeutic intervention were highlighted.

The traditional functions of cytoskeletal-associated proteins (CAPs) in line with polymerization and stabilization of the cytoskeleton have evolved and are currently underrated in oncology. Although therapeutic drugs have been developed to target the cytoskeletal components directly in cancer treatment, several recently established therapeutic agents designed for new targets block the proliferation of cancer cells and suppress resistance to existing target agents. It would seem like these targets only work toward inhibiting the polymerization of cytoskeletal components or hindering mitotic spindle formation in cancer cells, but a large body of literature points to CAPs and their culpability in cell signaling, molecular conformation, organelle trafficking, cellular metabolism, and genomic modifications. Here, we review those underappreciated functions of CAPs, and we delineate the implications of cellular signaling instigated by evasive properties induced by aberrant expression of CAPs in response to stress or failure to exert normal functions. We present an analogy establishing CAPs as vulnerable targets for cancer systems and credible oncotargets. This review establishes a paradigm in which the cancer machinery may commandeer the conventional functions of CAPs for survival, drug resistance, and energy generation; an interesting feature overdue for attention.

Background Nuclear translocation of several oncogenic proteins have previously been reported, but neither the translocation of doublecortin (DCX) nor the mechanism involved has been studied. DCX is a neuronal microtubule-associated protein (MAP) that is crucial for adult neurogenesis and neuronal migration and has been associated with poor prognosis in gliomas. Methods We probed DCX expression in different grades of glioma tissues and conventional cells via western blotting. Then we analyzed the expression pattern in the Oncomine cancer profiling database. Confocal Immunofluorescence was used to detect DCX expression in the cellular compartments, while subcellular fractionation was probed via western blotting. Pulse shape height analysis was utilized to verify DCX localization in a larger population of cells. Co-immunoprecipitation was used in detecting DCX-import receptors interactions. To probe for DCX functions, stable cells expressing high DCX expression or knockdown were generated using CRISPR-Cas9 viral transfection, while plasmid site-directed mutant constructs were used to validate putative nuclear localization sequence (NLS) predicted via conventional algorithms and comparison with classical NLSs. in-silico modeling was performed to validate DCX interactions with import receptors via the selected putative NLS. Effects of DCX high expression, knockdown, mutation, and/or deletion of putative NLS sites were probed via Boyden’s invasion assay and wound healing migration assays, and viability was detected by CCK8 assays in-vitro, while xenograft tumor model was performed in nude mice. Results DCX undergoes nucleocytoplasmic movement via the RanGTPase signaling pathway with an NLS located on the N-terminus between serine47-tyrosine70. This translocation could be stimulated by MARK’s phosphorylation of the serine 47 residue flanking the NLS due to aberrant expression of glial cell line-derived neurotrophic factor (GDNF). High expression and nuclear accumulation of DCX improve invasive glioma abilities in-vitro and in-vivo. Moreover, knocking down or blocking DCX nuclear import attenuates invasiveness and proliferation of glioma cells. Conclusion Collectively, this study highlights a remarkable phenomenon in glioma, hence revealing potential glioma dependencies on DCX expression, which is amenable to targeted therapy. Graphical Abstract