Hypoxia-Inducible Factor-1α Activity as a Switch for Glioblastoma Responsiveness to Temozolomide

Abstract

RationaleThe activity of the transcription factor, hypoxia-inducible factor (HIF)-1α, is a common driver of a number of the pathways involved in the aggressiveness of glioblastomas (GBMs), and it has been suggested that the reduction in this activity observed, soon after the administration of temozolomide (TMZ), can be a biomarker of an early response in GBM models. As HIF-1α is a tightly regulated protein, studying the processes involved in its downregulation could shed new light on the mechanisms underlying GBM sensitivity or resistance to TMZ.MethodsThe effect of HIF-1α silencing on cell responsiveness to TMZ was assessed in four genetically different human GBM cell lines by evaluating cell viability and apoptosis-related gene balance. LAMP-2A silencing was used to evaluate the contribution of chaperone-mediated autophagy (CMA) to the modulation of HIF-1α activity in TMZ-sensitive and TMZ-resistant cells.ResultsThe results showed that HIF-1α but not HIF-2α activity is associated with GBM responsiveness to TMZ: its downregulation improves the response of TMZ-resistant cells, while blocking CMA-mediated HIF-1α degradation induces resistance to TMZ in TMZ-sensitive cells. These findings are in line with the modulation of crucial apoptosis-related genes.ConclusionOur results demonstrate the central role played by HIF-1α activity in determining the sensitivity or resistance of GBMs to TMZ, and we suggest that CMA is the cellular mechanism responsible for modulating this activity after TMZ treatment.

Knockdown ATG4C inhibits gliomas progression and promotes temozolomide chemosensitivity by suppressing autophagic flux

“…In the treatment of glioma, cytotoxicity chemotherapeutics drugs including TMZ can induce autophagy, which may promote the development of treatment resistance [23][24][25]57]. In our study, we observed for the first time that ATG4C is involved in TMZ-induced autophagy, and depletion of ATG4C significantly increased the sensitivity of U87-MG and T98G cells to TMZ, which are thought to be TMZ sensitivity and resistance cells, respectively [58]. Selective and specific cytotoxicity to tumor cells is expected during glioma chemotherapy, which can increase the anti-tumor activity of TMZ with less toxic effects.…”

Autophagy in the Immunosuppressive Perivascular Microenvironment of Glioblastoma

“…In addition, quantitative proteomics analysis of isolated lysosomes from CMA-activated conditions in cancer cells has recently revealed a new role for CMA in the control of cell translation [114]. Importantly, up-regulated CMA may also assist chemoresistance of GB, making them more resistant to different stressors such as oxidative stress, hypoxia or even DNA damage agents [4,115]. Up-regulation of CMA in GB cells that are in contact with perivascular areas, not only favors their proliferation, but it may even interfere with the aberrant CMA up-regulation in tumor surrounding cells that benefits tumor survival and affects anti-tumor immune microenvironment responses [36].…”

Monocarboxylate Transporter 4 Regulates Glioblastoma Motility and Monocyte Binding Ability

“…Many recent studies have provided convincing evidence of strong correlations between elevated levels of HIF-1α and tumor metastasis, angiogenesis, and tumor resistance to therapy [14][15][16]. Emerging evidence suggests that HIF-1α inhibitors used in combination with standard chemotherapy improve the response of TMZ-resistant GBM cells [17]. Furthermore, silencing HIF-1α expression appears to inhibit the proliferation [18], invasion, and migration of GBM [19].…”