Translational and HIF-1α-Dependent Metabolic Reprogramming Underpin Metabolic Plasticity and Responses to Kinase Inhibitors and Biguanides

Laura Hulea; Simon-Pierre Gravel; Masahiro Morita; Marie Cargnello; Oro Uchenunu; Young Kyuen Im; Camille Lehuédé; Eric H Ma; Matthew Leibovitch; Shannon McLaughlan; Marie-José Blouin; Maxime Parisotto; Vasilios Papavasiliou; Cynthia Lavoie; Ola Larsson; Michael Ohh; Tiago Ferreira; Celia Greenwood; Gaëlle Bridon; Daina Avizonis; Gerardo Ferbeyre; Peter Siegel; Russell G Jones; William Muller; Josie Ursini-Siegel; Julie St-Pierre; Michael Pollak; Ivan Topisirovic

doi:10.1016/j.cmet.2018.09.001

Translational and HIF-1α-Dependent Metabolic Reprogramming Underpin Metabolic Plasticity and Responses to Kinase Inhibitors and Biguanides

Cell Metab. 2018 Dec 4;28(6):817-832.e8. doi: 10.1016/j.cmet.2018.09.001. Epub 2018 Sep 20.

Authors

Laura Hulea¹, Simon-Pierre Gravel², Masahiro Morita³, Marie Cargnello⁴, Oro Uchenunu⁵, Young Kyuen Im⁵, Camille Lehuédé⁶, Eric H Ma⁷, Matthew Leibovitch¹, Shannon McLaughlan¹, Marie-José Blouin⁸, Maxime Parisotto⁹, Vasilios Papavasiliou¹⁰, Cynthia Lavoie¹⁰, Ola Larsson¹¹, Michael Ohh¹², Tiago Ferreira¹³, Celia Greenwood¹⁴, Gaëlle Bridon¹⁰, Daina Avizonis¹⁰, Gerardo Ferbeyre¹⁵, Peter Siegel¹⁶, Russell G Jones⁷, William Muller¹⁷, Josie Ursini-Siegel¹⁸, Julie St-Pierre¹⁹, Michael Pollak²⁰, Ivan Topisirovic²¹

Affiliations

¹ Lady Davis Institute, SMBD JGH, McGill University, Montreal, QC H3A 1A3, Canada; Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H3A 1A3, Canada.
² Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada; Faculté de Pharmacie, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, QC, Canada.
³ Department of Molecular Medicine and Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; Institute of Resource Developmental and Analysis, Kumamoto University, Kumamoto 860-8111, Japan.
⁴ Lady Davis Institute, SMBD JGH, McGill University, Montreal, QC H3A 1A3, Canada; Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H3A 1A3, Canada; Centre de Recherche en Cancérologie de Toulouse, 31100 Toulouse, France.
⁵ Lady Davis Institute, SMBD JGH, McGill University, Montreal, QC H3A 1A3, Canada; Department of Experimental Medicine, McGill University, Montreal, QC H3A 1A3, Canada.
⁶ Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Experimental Medicine, McGill University, Montreal, QC H3A 1A3, Canada.
⁷ Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Physiology, McGill University, Montreal, QC H3A 1A3, Canada.
⁸ Lady Davis Institute, SMBD JGH, McGill University, Montreal, QC H3A 1A3, Canada.
⁹ Département de Chimie, Université de Montréal, Montréal, QC H3C 3J7, Canada.
¹⁰ Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada.
¹¹ Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, 171 16 Stockholm, Sweden.
¹² Department of Laboratory Medicine and Pathobiology and Department of Biochemistry, University of Toronto, Toronto, ON M5S1A8, Canada.
¹³ McGill University Centre for Research in Neuroscience, Montreal General Hospital, Montreal, QC H3G 1A4, Canada.
¹⁴ Lady Davis Institute, SMBD JGH, McGill University, Montreal, QC H3A 1A3, Canada; Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, QC H3A 1A3, Canada; Department of Human Genetics, McGill University, Montreal, QC H3A 1A3, Canada.
¹⁵ Département de Biochimie et Médecine Moléculaire, Université de Montréal, Montréal, QC H3C 3J7, Canada.
¹⁶ Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada.
¹⁷ Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada; Department of Experimental Medicine, McGill University, Montreal, QC H3A 1A3, Canada.
¹⁸ Lady Davis Institute, SMBD JGH, McGill University, Montreal, QC H3A 1A3, Canada; Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H3A 1A3, Canada; Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada; Department of Experimental Medicine, McGill University, Montreal, QC H3A 1A3, Canada.
¹⁹ Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, Microbiology, and Immunology, Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
²⁰ Lady Davis Institute, SMBD JGH, McGill University, Montreal, QC H3A 1A3, Canada; Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H3A 1A3, Canada; Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Experimental Medicine, McGill University, Montreal, QC H3A 1A3, Canada. Electronic address: michael.pollak@mcgill.ca.
²¹ Lady Davis Institute, SMBD JGH, McGill University, Montreal, QC H3A 1A3, Canada; Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada; Department of Experimental Medicine, McGill University, Montreal, QC H3A 1A3, Canada. Electronic address: ivan.topisirovic@mcgill.ca.

Abstract

There is increasing interest in therapeutically exploiting metabolic differences between normal and cancer cells. We show that kinase inhibitors (KIs) and biguanides synergistically and selectively target a variety of cancer cells. Synthesis of non-essential amino acids (NEAAs) aspartate, asparagine, and serine, as well as glutamine metabolism, are major determinants of the efficacy of KI/biguanide combinations. The mTORC1/4E-BP axis regulates aspartate, asparagine, and serine synthesis by modulating mRNA translation, while ablation of 4E-BP1/2 substantially decreases sensitivity of breast cancer and melanoma cells to KI/biguanide combinations. Efficacy of the KI/biguanide combinations is also determined by HIF-1α-dependent perturbations in glutamine metabolism, which were observed in VHL-deficient renal cancer cells. This suggests that cancer cells display metabolic plasticity by engaging non-redundant adaptive mechanisms, which allows them to survive therapeutic insults that target cancer metabolism.

Keywords: HIF-1α; biguanide; cancer; kinase inhibitor; mRNA translation; mTORC1; metabolic plasticity; metabolism; non-essential amino acids.

Publication types

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

MeSH terms

Adaptor Proteins, Signal Transducing / metabolism
Amino Acids / metabolism
Animals
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Biguanides / pharmacology
Cell Cycle Proteins
Drug Resistance, Neoplasm*
Eukaryotic Initiation Factors / metabolism
Gene Expression Regulation, Neoplastic
HCT116 Cells
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
K562 Cells
Mechanistic Target of Rapamycin Complex 1 / metabolism
Mice
Mice, Nude
Neoplasms* / drug therapy
Neoplasms* / metabolism
Phosphoproteins / metabolism
Protein Kinase Inhibitors / pharmacology
RNA, Messenger / metabolism
Signal Transduction / drug effects*
Xenograft Model Antitumor Assays

Substances

Adaptor Proteins, Signal Transducing
Amino Acids
Biguanides
Cell Cycle Proteins
EIF4EBP1 protein, human
EIF4EBP2 protein, human
Eukaryotic Initiation Factors
HIF1A protein, human
Hypoxia-Inducible Factor 1, alpha Subunit
Phosphoproteins
Protein Kinase Inhibitors
RNA, Messenger
Mechanistic Target of Rapamycin Complex 1

Abstract

Publication types

MeSH terms

Substances

Grants and funding