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.

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
  • 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
  • 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