Effect of glycolysis inhibition by miR-448 on glioma radiosensitivity

Abstract

OBJECTIVEAlthough glucose metabolism reengineering is a typical feature of various tumors, including glioma, key regulators of glycolytic reprogramming are still poorly understood. The authors sought to investigate whether glycolysis inhibition by microRNA (miR)–448 increases radiosensitivity in glioma cells.METHODSThe authors used glioma tissue samples from glioma patients, cells from glioblastoma (GBM) cell lines and normal human astrocyte cells, and subcutaneous tumor–bearing U87 cells in mice to examine the effects of signaling regulation by miR-448 in the response of glioma tissues and cells to radiation treatment. Techniques used for investigation included bioinformatics analyses, biochemical assays, luciferase reporter assays, and establishment of subcutaneous tumors in a mouse model. Glucose consumption, LDH activity, and cellular ATP were measured to determine the ability of glioma cells to perform glycolysis. Expression of HIF-1α was measured as a potential target gene of miR-448 in glycolysis.RESULTSmiR-448 was detected and determined to be significantly downregulated in both glioma tissues from glioma patients and GBM cell lines. Furthermore, miR-448 acted as a tumor-inhibiting factor and suppressed glycolysis in glioma by negatively regulating the activity of HIF-1α signaling and then interfering with its downstream regulators relative to glycolysis, HK1, HK2, and LDHA. Interestingly, overexpression of miR-448 increased the x-radiation sensitivity of glioma cells. Finally, in in vivo experiments, subcutaneous tumor–bearing U87 cells in a mouse model verified that high expression of miR-448 also enhanced glioma radiosensitivity via inhibiting glycolytic factors.CONCLUSIONSmiR-448 can promote radiosensitivity by inhibiting HIF-1α signaling and then negatively controlling the glycolysis process in glioma. A newly identified miR-448–HIF-1α axis acts as a potentially valuable therapeutic target that may be useful in overcoming radioresistance in glioma treatment.

Non-Coding RNAs in Cancer Radiosensitivity: MicroRNAs and lncRNAs as Regulators of Radiation-Induced Signaling Pathways

“…A similar mechanism was reported for miR-448 in glioma cells. miR-448 directly targeted HIF-1α, which led to inhibition of proteins involved in glycolysis: HK1, HK2, LDHA [64]. miR-133b sensitized NSCLC cells to IR and negatively regulated glycolysis.…”

“…Mcl-1 Apoptosis GBM, cervical cancer [51] miR-199a Beclin-1, DRAM1 Autophagy Breast cancer [52] miR-200c UBQLN1 Autophagy Breast cancer [53] miR-203a ATM Apoptosis, cell cycle, migration Ovarian cancer [54] miR-205 TP53INP1 Autophagy Prostate cancer [26] miR-214 ATG12 Autophagy CRC * [55] miR-216a Beclin-1 Autophagy Pancreatic cancer * [56] miR-222 RAD51 DSB repair Ovarian cancer [34] miR-223 ATM -Glioma * [57] miR-301a Wnt Wnt/β-catenin, migration ESCC [58] miR-302a AKT, RAD52 -Breast cancer * [59] miR-320a STAT3 Apoptosis, metastasis NSCLC * [60] β-catenin Wnt/β-catenin Cervical cancer [61] miR-324-3p Wnt2B Wnt/ β-catenin NPC [62] miR-421 ATM DSB repair SCC [63] miR-448 HIF-1α Glycolysis Glioma [64] miR-449a LDHA Glycolysis, apoptosis Lung cancer [65] miR-449a c-MYC Cell cycle Prostate cancer * [66] miR-450a DUSP10 Autophagy ESCC * [67] miR-634 STAT3 Apoptosis Breast cancer [68] miR…”

MiRNAs in Radiotherapy Resistance of Nasopharyngeal Carcinoma

“…The reasons at the gene level include the following two types: the decrease of apoptotic genes or the increase of the expression of anti-apoptotic genes and proliferating genes, and the enhancement of genes related to DNA damage repair, or the expression of cell cycle regulatory genes is dysregulated [6,7,17,18]. Many studies have shown that miRNAs participate in tumor radiation resistance through the above mechanisms [19][20][21].…”

<p>Emerging Roles and Therapeutic Interventions of Aerobic Glycolysis in Glioma</p>

“…160 Regarding the effects of chemotherapy and radiotherapy, HIF-1α signaling participated in regulating effectiveness of irradiation and temozolomide of glioma via the glycolytic process. 158,161 Surprisingly, more and more regulators have been detected in the functional activities of HIF-1α in glioma. The hypoxic condition could contribute to the upregulation of HIF-1α via elevating the expression of TIGAR, while prolyl hydroxylation of HIF-1α would happen under normoxic conditions.…”