Altered energy metabolism is a hallmark of tumors aiming at supplying necessary nutrients for tumorigenesis and development. These redirected metabolic pathways associated with carbohydrate, lipid and amino acid are orchestrated not only by carcinogenic proteins but by non-coding RNAs. Among them, circular RNA (circRNA), as a kind of novel identified non-coding RNAs, has become the focus of attention. Through binding with corresponding microRNAs or directly contacting proteins, circRNA plays a primarily important role in regulating cellular metabolism. Herein, we analyze the emerging findings and select circRNAs contributing to mutant glycolysis, lipogenesis and lipolysis, glutam inolysis, and oxidative respiration to deepen the understanding about the cancer metabolic regulatory network. In addition, we also discuss the possibility of circRNAs exerting their functions via exosomes and cancer stem cells. Owing to their unique structures and wide impacts, circRNAs may help reap huge fruits in developing clinical treatments targeting cancer metabolism.

/pdf/circrnas-in-cancer-metabolism-a-review-22pazxxod2.pdf

CircRNAs in cancer metabolism: a review

An important hallmark in cancer cells is the increase in glucose uptake GLUT1 is an important target in cancer treatment because cancer cells upregulate GLUT1, a membrane protein that facilitates the basal uptake of glucose in most cell types, to ensure the flux of sugar into metabolic pathways The dysregulation of GLUT1 is associated with numerous disorders, including cancer and metabolic diseases There are natural products emerging as a source for inhibitors of glucose uptake, and resveratrol is a molecule of natural origin with many properties that acts as antioxidant and antiproliferative in malignant cells In the present review, we discuss how GLUT1 is involved in the general scheme of cancer cell metabolism, the mechanism of glucose transport, and the importance of GLUT1 structure to understand the inhibition process Then, we review the current state-of-the-art of resveratrol and other natural products as GLUT1 inhibitors, focusing on those directed at treating different types of cancer Targeting GLUT1 activity is a promising strategy for the development of drugs aimed at treating neoplastic growth

https://www.mdpi.com/1422-0067/20/13/3374/pdf

Glut 1 in Cancer Cells and the Inhibitory Action of Resveratrol as A Potential Therapeutic Strategy.

Background
Glucose transporter 1 (GLUT1) plays a critical role in tumorigenesis and tumor progression in multiple cancer types. However, the specific function and clinical significance of GLUT1 in prostate cancer (PCa) are still unclear. Therefore, in this study, we investigated the role of GLUT1 in PCa.

Methods
GLUT1 protein levels in prostate cancer tissue and tumor-adjacent normal tissues were measured and compared. Furthermore, real-time PCR and Western blot analysis were both used to detect GLUT1 expression levels in different PCa cell lines. Flow cytometry and cell-based assays, such as a glucose uptake and lactate secretion assay, CCK-8 assay, and transwell migration and wound healing assay, were used to monitor cancer cell cycle distribution, glycolysis, proliferation, and motility, respectively. Moreover, a mouse tumor xenograft model was used to investigate the role of GLUT1 in tumor progression in vivo.

Results
GLUT1 expression levels are higher in PCa tissues than in tumor-adjacent normal tissues. The results from real-time PCR and Western blot analysis revealed a similar increase in the GLUT1 expression levels in PCa cell lines. Moreover, knockdown of GLUT1 inhibits cell glycolysis and proliferation and leads to cell cycle arrest at G2/M phase in the 22RV1 cell line but not in the PC3 cell line. In vivo experiments further confirmed that GLUT1 knockdown inhibits the growth of tumors derived from the 22RV1 cell line. In addition, we also showed that GLUT1 knockdown has no effect on cell migration in vitro.

Conclusions
GLUT1 may play an important role in PCa progression via mediating glycolysis and proliferation. Our study also indicated a potential crosstalk between GLUT1-mediated glycolysis and androgen sensitivity in PCa.

GLUT1 regulates cell glycolysis and proliferation in prostate cancer.

Aerobic glycolysis (the Warburg effect) is a robust metabolic hallmark of most tumors, including oral squamous cell carcinoma (OSCC). Glucose transporter 1 (GLUT1), a major glucose transporter regulating the glucose uptake, is upregulated in OSCC and participated in the cell glycolysis of OSCC. The deregulation and function of noncoding RNAs in cancers have been widely reported. Reportedly, hsa_circular RNA (circRNA)_100290 (circ_SLC30A7) is significantly upregulated (fold change = 6.91, p < 0.0000001) in OSCC. According to online tools prediction (miRWalk, miRanda, and Targetscan), miR-378a could simultaneously target circRNA_100290 and GLUT1. Herein, the expression of circRNA_100290 and GLUT1 remarkably increased in oral tumor tissue specimens and cells. In OSCC cell lines, cell proliferation and glycolysis could be remarkably downregulated by circRNA_100290 silence, which could be rescued by GLUT1 overexpression. Conversely, miR-378a expression could be remarkably inhibited in tumor tissue specimens and cells. The effect of miR-378a overexpression on OSCC cells was similar to those of circRNA_100290 silence. miR-378a directly bound to circRNA_100290 and GLUT1 3'-untranslated region, circRNA_100290 could remarkably relieve miR-378a-induced inhibition on GLUT1 via acting as a competing endogenous RNA (ceRNA). miR-378a inhibition remarkably attenuated the effect of circRNA_100290 silence on cell proliferation and glycolysis in OSCC cell lines. In summary, circRNA_100290 serves as a ceRNA to counteract miR-378a-mediated GLUT1 suppression, thus promoting glycolysis and cell proliferation in OSCC. We provide a reliable experimental basis for understanding the mechanism of cell growth and glycolysis deregulation in OSCC.

Circle RNA hsa_circRNA_100290 serves as a ceRNA for miR-378a to regulate oral squamous cell carcinoma cells growth via Glucose transporter-1 (GLUT1) and glycolysis.

Regulation of Glycolysis by Non-coding RNAs in Cancer: Switching on the Warburg Effect.

Objective: Osteosarcoma (OS) is the most common malignant bone tumor in children and young adults. Many studies have shown that microRNAs play a critical role in proliferation and metastasis with this tumour type. However, whether aberrant expression might contribute to a metabolism switch in osteosarcoma cases is not clearly understood. In this study, we explored expression and function of miR-150 in osteosarcoma cells. Materials and methods: Expression of miR-150 was assessed by real-time PCR in cell lines and human patient tissues. Scramble siRNA, miR-150 inhibitor, and miR-150 mimics were transfected into osteosarcoma cells to determine their effects on proliferation rate, glucose uptake and lactate secretion. Finally, the relationship between Glut1 and the miR-150 level was explored by luciferase reporter assay and western blotting. Result: miR-150 was consistently decreased in cell lines and osteosarcoma tissues as compared to osteoblast cells and normal bone. Ectopic overexpression of miR-150 inhibited osteosarcoma cell proliferation and suppressed glucose uptake and lactate secretion. Loss of function of miR-150, on the other hand, enhanced osteosarcoma cell proliferation and increased glucose uptake and lactate secretion. Western blot and luciferase reporter assays showed that miR-150 may function by regulating Glut1 expression. Conclusion: These data suggest that miR-150 is involved in regulation of glycolysis in osteosarcoma cells by influencing Glut1 expression.

http://journal.waocp.org/article_45412_300b1d18b746a5025f31ec215924f89a.pdf

Mir-150 Up-Regulates Glut1 and Increases Glycolysis in Osteosarcoma Cells

Aim The aim of this study is to explore the function of miR-20a in osteosarcoma. Materials & methods miR-20a expression was measured by real-time PCR. miR-20a mimics, inhibitor and scramble siRNA were transfected into osteosarcoma cells to observe effects on colony formation and tumor growth. Moreover, relationships of miR-20a with TAK1 were investigated by western blot and luciferase activity. Results We found that miR-20a was downregulated in osteosarcoma, and overexpression of miR-20a reduced colony formation and tumor growth. Furthermore, the data revealed that the function of miR-20a was probably exerted via targeting the TAK1 expression. Overexpression of miR-20a sensitizes the osteosarcoma cells to chemotherapeutic drugs. Conclusion Our data identify the role of miR-20a in osteosarcoma growth, indicating its potential application in chemotherapy.

Yanqing Zhao

Papers

Mir-150 Up-Regulates Glut1 and Increases Glycolysis in Osteosarcoma Cells

miRNA-20a upregulates TAK1 and increases proliferation in osteosarcoma cells.

Proliferation of bovine myoblast by LncPRRX1 via regulation of the miR-137/CDC42 axis.