title: lncRNA NBR2 modulates cancer cell sensitivity to phenformin through GLUT1.
abstract: Biguanides, including metformin (widely used in diabetes treatment) and phenformin, are AMP-activated protein kinase (AMPK) activators and potential drugs for cancer treatment. A more in-depth understanding of how cancer cells adapt to biguanide treatment may provide important therapeutic implications to achieve more effective and rational cancer therapies. NBR2 is a glucose starvation-induced long non-coding RNA (lncRNA) that interacts with AMPK and regulates AMPK activity upon glucose starvation. Here we show that phenformin treatment induces NBR2 expression, and NBR2 deficiency sensitizes cancer cells to phenformin-induced cell death. Surprisingly, unlike glucose starvation, phenformin does not induce NBR2 interaction with AMPK, and correspondingly, NBR2 deficiency does not affect phenformin-induced AMPK activation. We further reveal that NBR2 depletion attenuates phenformin-induced glucose transporter GLUT1 expression and glucose uptake. GLUT1 deficiency sensitizes cancer cells to phenformin-induced cell death, whereas GLUT1 restoration in NBR2 deficient cells rescues the increased cell death upon phenformin treatment. Together, the results of our study reveal that NBR2-GLUT1 axis may serve as an adaptive response in cancer cells to survive in response to phenformin treatment, and identify a novel mechanism coupling lncRNA to biguanide-mediated biology.
authors: a Department of Experimental Radiation Oncology , University of Texas MD Anderson Cancer Center , Houston , TS , USA.
authors: Xiaowen
authors: X
authors: Liu
authors: a Department of Experimental Radiation Oncology , University of Texas MD Anderson Cancer Center , Houston , TS , USA.|b Department of Molecular and Cellular Oncology , University of Texas MD Anderson Cancer Center , Houston , TX , USA.|c Program of Genes and Development, and Program of Cancer Biology , University of Texas Graduate School of Biomedical Sciences , Houston , TX , USA.
authors: Boyi
authors: B
authors: Gan
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology*; D010629:Phenformin / Q000494:pharmacology*; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014157:Transcription Factors
chemical_list: D051272:Glucose Transporter Type 1; D046912:Multiprotein Complexes; C107422:NBR2 lncRNA, human; D062085:RNA, Long Noncoding; C495677:SLC2A1 protein, human; D014157:Transcription Factors; D010629:Phenformin; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose
keywords: AMPK; GLUT1; NBR2; biguanide; long non-coding RNA; phenformin