Bioengineered miR-328-3p modulates GLUT1-mediated glucose uptake and metabolism to exert synergistic antiproliferative effects with chemotherapeutics

• 来源期刊: 药学学报（英文版）
• 关键词: Bioengineered RNA MiR-328 LAT1 GLUT 1 Chemosensitivity Cancer
• 年，卷（期）: 2020,（1）
• 页码范围: 159-170
• 页数: 12页
• 语种: 英文

摘要

MicroRNAs (miRNAs or miRs) are small noncoding RNAs derived from genome to control target gene expression.Recently we have developed a novel platform permitting high-yield production of bioengineered miRNA agents (BERA).This study is to produce and utilize novel fully-humanized BERA/miR-328-3p molecule (hBERA/miR-328) to delineate the role of miR-328-3p in controlling nutrient uptake essential for cell metabolism.We first demonstrated successful high-level expression of hBERA/miR-328 in bacteria and purification to high degree of homogeneity (＞98％).Biologic miR-328-3p prodrug was selectively processed to miR-328-3p to suppress the growth of highly-proliferative human osteosarcoma (OS) cells.Besides glucose transporter protein type 1,gene symbol solute carrier family 2 member l (GLUT1/SLC2A1),we identified and verified large neutral amino acid transporter 1,gene symbol solute carrier family 7 member 5 (LAT1/SLC7A5) as a direct target for miR-328-3p.While reduction of LAT1 protein levels by miR-328-3p did not alter homeostasis of amino acids within OS cells,suppression of GLUT1 led to a significantly lower glucose uptake and decline in intracellular levels of glucose and glycolytic metabolite lactate.Moreover,combination treatment with hBERA/miR-328 and cisplatin or doxorubicin exerted a strong synergism in the inhibition of OS cell proliferation.These findings support the utility of novel bioengineered RNA molecules and establish an important role of miR-328-3p in the control of nutrient transport and homeostasis behind cancer metabolism.