title: Tumour-associated mutant p53 drives the Warburg effect.
abstract: Tumour cells primarily utilize aerobic glycolysis for energy production, a phenomenon known as the Warburg effect. Its mechanism is not well understood. The tumour suppressor gene p53 is frequently mutated in tumours. Many tumour-associated mutant p53 (mutp53) proteins not only lose tumour suppressive function but also gain new oncogenic functions that are independent of wild-type p53, defined as mutp53 gain of function (GOF). Here we show that tumour-associated mutp53 stimulates the Warburg effect in cultured cells and mutp53 knockin mice as a new mutp53 GOF. Mutp53 stimulates the Warburg effect through promoting GLUT1 translocation to the plasma membrane, which is mediated by activated RhoA and its downstream effector ROCK. Inhibition of RhoA/ROCK/GLUT1 signalling largely abolishes mutp53 GOF in stimulating the Warburg effect. Furthermore, inhibition of glycolysis in tumour cells greatly compromises mutp53 GOF in promoting tumorigenesis. Thus, our results reveal a new mutp53 GOF and a mechanism for controlling the Warburg effect.
authors.affiliation: 1] Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers State University of New Jersey, New Brunswick, New Jersey 08902, USA [2].
authors.forename: Cen
authors.initials: C
authors.lastname: Zhang
authors.affiliation: 1] Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers State University of New Jersey, New Brunswick, New Jersey 08902, USA [2].
authors.forename: Juan
authors.initials: J
authors.lastname: Liu
authors.affiliation: 1] Department of Pediatrics, Rutgers Cancer Institute of New Jersey, Rutgers State University of New Jersey, New Brunswick, New Jersey 08902, USA [2] Laboratory of Hepatosplenic Surgery, First Affiliated Hospital of Harbin Medical University, Harbin 150086, China [3].
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, New Jersey 08902, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Wu
authors.affiliation: 1] Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers State University of New Jersey, New Brunswick, New Jersey 08902, USA [2] Department of Pediatrics, Rutgers Cancer Institute of New Jersey, Rutgers State University of New Jersey, New Brunswick, New Jersey 08902, USA.
authors.forename: Yuhan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: 1] Department of Pediatrics, Rutgers Cancer Institute of New Jersey, Rutgers State University of New Jersey, New Brunswick, New Jersey 08902, USA [2] Laboratory of Hepatosplenic Surgery, First Affiliated Hospital of Harbin Medical University, Harbin 150086, China.
authors.forename: Xuehui
authors.initials: X
authors.lastname: Hong
authors.affiliation: Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers State University of New Jersey, New Brunswick, New Jersey 08902, USA.
authors.forename: Meihua
authors.initials: M
authors.lastname: Lin
authors.affiliation: 1] Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers State University of New Jersey, New Brunswick, New Jersey 08902, USA [2] Department of Pediatrics, Rutgers Cancer Institute of New Jersey, Rutgers State University of New Jersey, New Brunswick, New Jersey 08902, USA.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Yu
authors.affiliation: Laboratory of Hepatosplenic Surgery, First Affiliated Hospital of Harbin Medical University, Harbin 150086, China.
authors.forename: Lianxin
authors.initials: L
authors.lastname: Liu
authors.affiliation: The Institute for Advanced Study, Princeton, New Jersey 08540, USA.
authors.forename: Arnold J
authors.initials: AJ
authors.lastname: Levine
authors.affiliation: 1] Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers State University of New Jersey, New Brunswick, New Jersey 08902, USA [2] Department of Pediatrics, Rutgers Cancer Institute of New Jersey, Rutgers State University of New Jersey, New Brunswick, New Jersey 08902, USA.
authors.forename: Wenwei
authors.initials: W
authors.lastname: Hu
authors.affiliation: Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers State University of New Jersey, New Brunswick, New Jersey 08902, USA.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Feng
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D016158:Genes, p53; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006801:Humans; D007773:Lactates / Q000097:blood; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D058494:Walker-Warburg Syndrome / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D000199:Actins; D051272:Glucose Transporter Type 1; D007773:Lactates; C495677:SLC2A1 protein, human; D016159:Tumor Suppressor Protein p53; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein; D005947:Glucose