Abstract
Drug resistance is one of the major obstacles in glioblastoma (GBM) treatments using temozolomide (TMZ) based conventional chemotherapy. Recent studies revealed that Hexokinase 2 (HK2)‐mediated glycolysis is one of the sources, as the association of chemoresistance and the expression of HK2 was confirmed in multiple cancers. However, there has been little knowledge of the functional contribution of HK2 to TMZ resistance in GBM. In our study, we found that HK2 expression is crucial for GBM proliferation and chemoresistance. In contrast to the healthy brain, HK2 expression is much higher in human GBM, especially in those patients with GBM recurrence. High HK2 expression is negatively related to the overall survival in GBM patients. HK2 depletion in GBM cells suppressed the GBM cell proliferation and increased sensitivity to TMZ‐induced apoptosis. Both HK2‐mediated glycolysis and mitochondria permeability transition pore opening (MPTP) were associated with its function in chemoresistance. Furthermore, we also revealed that the abnormal expression of HK2 was modulated by the expression of HOTAIR, a long non‐coding RNA (lncRNA). The absence of HOTAIR in GBM cells suppressed the HK2 expression in protein and mRNA level and, therefore, inhibited the cell proliferation and enhanced the cytotoxicity of TMZ both in vivo and in vitro. HOTAIR promoted the expression of HK2 by targeting mir‐125, which suppressed the GBM cell proliferation and increased the TMZ‐induced apoptosis. These findings shed light on a new therapeutic strategy in modulating HOTAIR/miR‐125, which may interfere with the expression of HK2, and enhance the therapeutic sensitivity of GBM to TMZ.
Highlights
Glioblastoma multiforme, as one of the most lethal cancers, is the primary gliomas and the most common malignant central nervous system tumour in adult patients.[1]
Since our data suggested that high Hexokinase 2 (HK2) expression might contribute to GBM chemoresistance, we further studied the influence of HK2 depletion on the proliferation and response to TMZ treatment in GBM cells
Since HK2 is an vital regulator of glycolysis, which has been previously reported to promote cancer progression,[26,27] we suggested that HK2-driven glycolysis was involved during the process of the chemoresistance of GBM
Summary
Glioblastoma multiforme, as one of the most lethal cancers, is the primary gliomas and the most common malignant central nervous system tumour in adult patients.[1]. HK2 was well documented to play an essential part in the Warburg effect and to be a metabolic target in cancer treatment.[11] The increase in mitochondrial-bound HK2 exhibited cancer-promoting effects by inducing glycolysis and the inhibition against apoptosis.[12] In terms of GBM, HK2 was reported to mediate the glycolysis and suppressed the sensitivity to radiation and temozolomide-based chemotherapy.[13] In respect of the therapeutic potentials of HK2, understanding the mechanism and directly and selectively targeting the HK2 may provide a feasible strategy in GBM treatment. Targeting HOTAIR/miR-125 pathway efficiently suppressed the expression of HK2 and sensitized the GBM cells to TMZ-induced cell death, which provides a new approach against drug resistance of GBM
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