Targeting the Warburg effect via LDHA inhibition engages ATF4 signaling for cancer cell survival

EMBO J. 2018 Oct 15;37(20):e99735. doi: 10.15252/embj.201899735. Epub 2018 Sep 12.

Abstract

Nutrient restriction reprograms cellular signaling and metabolic network to shape cancer phenotype. Lactate dehydrogenase A (LDHA) has a key role in aerobic glycolysis (the Warburg effect) through regeneration of the electron acceptor NAD+ and is widely regarded as a desirable target for cancer therapeutics. However, the mechanisms of cellular response and adaptation to LDHA inhibition remain largely unknown. Here, we show that LDHA activity supports serine and aspartate biosynthesis. Surprisingly, however, LDHA inhibition fails to impact human melanoma cell proliferation, survival, or tumor growth. Reduced intracellular serine and aspartate following LDHA inhibition engage GCN2-ATF4 signaling to initiate an expansive pro-survival response. This includes the upregulation of glutamine transporter SLC1A5 and glutamine uptake, with concomitant build-up of essential amino acids, and mTORC1 activation, to ameliorate the effects of LDHA inhibition. Tumors with low LDHA expression and melanoma patients acquiring resistance to MAPK signaling inhibitors, which target the Warburg effect, exhibit altered metabolic gene expression reminiscent of the ATF4-mediated survival signaling. ATF4-controlled survival mechanisms conferring synthetic vulnerability to the approaches targeting the Warburg effect offer efficacious therapeutic strategies.

Keywords: LDHA; ATF4; Warburg; aspartate; mTORC1.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Activating Transcription Factor 4 / genetics
  • Activating Transcription Factor 4 / metabolism*
  • Amino Acid Transport System ASC / genetics
  • Amino Acid Transport System ASC / metabolism
  • Aspartic Acid / biosynthesis
  • Aspartic Acid / genetics
  • Cell Line, Tumor
  • Cell Proliferation*
  • Cell Survival
  • Glycolysis*
  • Humans
  • L-Lactate Dehydrogenase / antagonists & inhibitors
  • L-Lactate Dehydrogenase / genetics
  • L-Lactate Dehydrogenase / metabolism*
  • Mechanistic Target of Rapamycin Complex 1 / genetics
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Melanoma / genetics
  • Melanoma / metabolism*
  • Melanoma / pathology
  • Minor Histocompatibility Antigens / genetics
  • Minor Histocompatibility Antigens / metabolism
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Serine / biosynthesis
  • Serine / genetics
  • Signal Transduction*

Substances

  • ATF4 protein, human
  • Amino Acid Transport System ASC
  • Minor Histocompatibility Antigens
  • Neoplasm Proteins
  • SLC1A5 protein, human
  • Activating Transcription Factor 4
  • Aspartic Acid
  • Serine
  • L-Lactate Dehydrogenase
  • LDHA protein, human
  • EIF2AK4 protein, human
  • Mechanistic Target of Rapamycin Complex 1
  • Protein-Serine-Threonine Kinases