Gain-of-function mutant p53 promotes cell growth and cancer cell metabolism via inhibition of AMPK activation

Ge Zhou; Jiping Wang; Mei Zhao; Tong-Xin Xie; Noriaki Tanaka; Daisuke Sano; Ameeta A Patel; Alexandra M Ward; Vlad C Sandulache; Samar A Jasser; Heath D Skinner; Alison Lea Fitzgerald; Abdullah A Osman; Yongkun Wei; Xuefeng Xia; Zhou Songyang; Gordon B Mills; Mien-Chie Hung; Carlos Caulin; Jiyong Liang; Jeffrey N Myers

doi:10.1016/j.molcel.2014.04.024

Gain-of-function mutant p53 promotes cell growth and cancer cell metabolism via inhibition of AMPK activation

Mol Cell. 2014 Jun 19;54(6):960-974. doi: 10.1016/j.molcel.2014.04.024. Epub 2014 May 22.

Authors

Ge Zhou¹, Jiping Wang², Mei Zhao², Tong-Xin Xie², Noriaki Tanaka², Daisuke Sano², Ameeta A Patel², Alexandra M Ward², Vlad C Sandulache², Samar A Jasser², Heath D Skinner², Alison Lea Fitzgerald², Abdullah A Osman², Yongkun Wei³, Xuefeng Xia⁴, Zhou Songyang⁵, Gordon B Mills⁶, Mien-Chie Hung⁷, Carlos Caulin⁸, Jiyong Liang⁶, Jeffrey N Myers⁹

Affiliations

¹ Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: gzhou@mdanderson.org.
² Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
³ Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁴ Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Diabetes Research, Methodist Hospital Research Institute, Houston, TX 77030, USA.
⁵ Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA; School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China.
⁶ Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁷ Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Graduated Institute of Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan.
⁸ Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁹ Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: jmyers@mdanderson.org.

Abstract

Many mutant p53 proteins (mutp53s) exert oncogenic gain-of-function (GOF) properties, but the mechanisms mediating these functions remain poorly defined. We show here that GOF mutp53s inhibit AMP-activated protein kinase (AMPK) signaling in head and neck cancer cells. Conversely, downregulation of GOF mutp53s enhances AMPK activation under energy stress, decreasing the activity of the anabolic factors acetyl-CoA carboxylase and ribosomal protein S6 and inhibiting aerobic glycolytic potential and invasive cell growth. Under conditions of energy stress, GOF mutp53s, but not wild-type p53, preferentially bind to the AMPKα subunit and inhibit AMPK activation. Given the importance of AMPK as an energy sensor and tumor suppressor that inhibits anabolic metabolism, our findings reveal that direct inhibition of AMPK activation is an important mechanism through which mutp53s can gain oncogenic function.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases / antagonists & inhibitors
AMP-Activated Protein Kinases / metabolism*
Acetyl-CoA Carboxylase / metabolism
Animals
Antimetabolites, Antineoplastic / pharmacology
Carcinoma, Squamous Cell / genetics*
Cell Movement / genetics
Cell Proliferation
Energy Metabolism / genetics*
Enzyme Activation / genetics
Fluorouracil / pharmacology
Head and Neck Neoplasms / genetics*
Humans
Mice
Mice, Nude
Neoplasm Invasiveness / genetics
Neoplasm Transplantation
Protein Binding / genetics
RNA Interference
RNA, Small Interfering
Ribosomal Protein S6 / metabolism
Signal Transduction / genetics
Spheroids, Cellular / cytology
Squamous Cell Carcinoma of Head and Neck
Transplantation, Heterologous
Tumor Cells, Cultured
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism*

Substances

Antimetabolites, Antineoplastic
RNA, Small Interfering
Ribosomal Protein S6
TP53 protein, human
Tumor Suppressor Protein p53
AMP-Activated Protein Kinases
Acetyl-CoA Carboxylase
Fluorouracil

Abstract

Publication types

MeSH terms

Substances

Grants and funding