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

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

Author information

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

PMID:
30244971
DOI:
10.1016/j.cmet.2018.09.001

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