title: RRAD inhibits the Warburg effect through negative regulation of the NF-κB signaling.
abstract: Cancer cells preferentially use aerobic glycolysis to meet their increased energetic and biosynthetic demands, a phenomenon known as the Warburg effect. Its underlying mechanism is not fully understood. RRAD, a small GTPase, is a potential tumor suppressor in lung cancer. RRAD expression is frequently down-regulated in lung cancer, which is associated with tumor progression and poor prognosis. Recently, RRAD was reported to repress the Warburg effect, indicating that down-regulation of RRAD expression is an important mechanism contributing to the Warburg effect in lung cancer. However, the mechanism by which RRAD inhibits the Warburg effect remains unclear. Here, we found that RRAD negatively regulates the NF-κB signaling to inhibit the GLUT1 translocation and the Warburg effect in lung cancer cells. Mechanically, RRAD directly binds to the p65 subunit of the NF-κB complex and inhibits the nuclear translocation of p65, which in turn negatively regulates the NF-κB signaling to inhibit GLUT1 translocation and the Warburg effect. Blocking the NF-κB signaling largely abolishes the inhibitory effects of RRAD on the translocation of GLUT1 to the plasma membrane and the Warburg effect. Taken together, our results revealed a novel mechanism by which RRAD negatively regulates the Warburg effect in lung cancer cells.
authors.affiliation: Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, State University of New Jersey, New Brunswick, NJ, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, State University of New Jersey, New Brunswick, NJ, USA.
authors.forename: Cen
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, State University of New Jersey, New Brunswick, NJ, USA.|Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Wu
authors.affiliation: Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, State University of New Jersey, New Brunswick, NJ, USA.
authors.forename: Meihua
authors.initials: M
authors.lastname: Lin
authors.affiliation: Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, State University of New Jersey, New Brunswick, NJ, USA.
authors.forename: Yingjian
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, State University of New Jersey, New Brunswick, NJ, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, State University of New Jersey, New Brunswick, NJ, USA.
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Yang
authors.affiliation: Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, State University of New Jersey, New Brunswick, NJ, USA.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Feng
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport / Q000187:drug effects; D034622:RNA Interference; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D051272:Glucose Transporter Type 1; D016328:NF-kappa B; C084355:RRAD protein, human; C495677:SLC2A1 protein, human; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D018631:ras Proteins
keywords: GLUT1; NF-κB; RRAD; p65; the Warburg effect