Therapy-induced DNA methylation inactivates MCT1 and renders tumor cells vulnerable to MCT4 inhibition

Cell Rep. 2021 Jun 1;35(9):109202. doi: 10.1016/j.celrep.2021.109202.

Abstract

Metabolic plasticity in cancer cells makes use of metabolism-targeting agents very challenging. Drug-induced metabolic rewiring may, however, uncover vulnerabilities that can be exploited. We report that resistance to glycolysis inhibitor 3-bromopyruvate (3-BrPA) arises from DNA methylation in treated cancer cells and subsequent silencing of the monocarboxylate transporter MCT1. We observe that, unexpectedly, 3-BrPA-resistant cancer cells mostly rely on glycolysis to sustain their growth, with MCT4 as an essential player to support lactate flux. This shift makes cancer cells particularly suited to adapt to hypoxic conditions and resist OXPHOS inhibitors and anti-proliferative chemotherapy. In contrast, blockade of MCT4 activity in 3-BrPA-exposed cancer cells with diclofenac or genetic knockout, inhibits growth of derived spheroids and tumors in mice. This study supports a potential mode of collateral lethality according to which metabolic adaptation of tumor cells to a first-line therapy makes them more responsive to a second-line treatment.

Keywords: 3-bromopyruvate; diclofenac; drug repurposing; epigenetic; metabolic plasticity; methylation; monocarboxylate transporter; tumor metabolism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Hypoxia / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Respiration / drug effects
  • DNA Methylation / genetics*
  • Down-Regulation / drug effects
  • Down-Regulation / genetics
  • Drug Resistance, Neoplasm / drug effects
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glycolysis / drug effects
  • Humans
  • Lactic Acid / metabolism
  • Mice
  • Models, Biological
  • Monocarboxylic Acid Transporters / antagonists & inhibitors*
  • Monocarboxylic Acid Transporters / genetics*
  • Monocarboxylic Acid Transporters / metabolism
  • Muscle Proteins / antagonists & inhibitors*
  • Muscle Proteins / metabolism
  • Phenotype
  • Promoter Regions, Genetic / genetics
  • Pyruvates / pharmacology*
  • Symporters / genetics*
  • Symporters / metabolism

Substances

  • Monocarboxylic Acid Transporters
  • Muscle Proteins
  • Pyruvates
  • SLC16A4 protein, human
  • Symporters
  • monocarboxylate transport protein 1
  • Lactic Acid
  • bromopyruvate