PKLR promotes colorectal cancer liver colonization through induction of glutathione synthesis

J Clin Invest. 2016 Feb;126(2):681-94. doi: 10.1172/JCI83587. Epub 2016 Jan 19.

Abstract

Colorectal cancer metastasis to the liver is a major cause of cancer-related death; however, the genes and pathways that govern this metastatic colonization event remain poorly characterized. Here, using a large-scale in vivo RNAi screen, we identified liver and red blood cell pyruvate kinase (PKLR) as a driver of metastatic liver colonization. PKLR expression was increased in liver metastases as well as in primary colorectal tumors of patients with metastatic disease. Evaluation of a murine liver colonization model revealed that PKLR promotes cell survival in the tumor core during conditions of high cell density and oxygen deprivation by increasing glutathione, the primary endogenous antioxidant. PKLR negatively regulated the glycolytic activity of PKM2, the major pyruvate kinase isoenzyme known to regulate cellular glutathione levels. Glutathione is critical for metastasis, and we determined that the rate-limiting enzyme of glutathione synthesis, GCLC, becomes overexpressed in patient liver metastases, promotes cell survival under hypoxic and cell-dense conditions, and mediates metastatic liver colonization. RNAi-mediated inhibition of glutathione synthesis impaired survival of multiple colon cancer cell lines, and pharmacological targeting of this metabolic pathway reduced colonization in a primary patient-derived xenograft model. Our findings highlight the impact of metabolic reprogramming within the niche as metastases progress and suggest clinical potential for targeting this pathway in colorectal cancer.

Publication types

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

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cell Line, Tumor
  • Colorectal Neoplasms / enzymology*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / pathology
  • Glutathione / biosynthesis*
  • Glutathione / genetics
  • Heterografts
  • Humans
  • Liver Neoplasms / enzymology*
  • Liver Neoplasms / genetics
  • Liver Neoplasms / pathology
  • Liver Neoplasms / secondary*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplasm Metastasis
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Neoplasm Transplantation
  • Pyruvate Kinase / genetics
  • Pyruvate Kinase / metabolism*
  • Thyroid Hormones / genetics
  • Thyroid Hormones / metabolism

Substances

  • Carrier Proteins
  • Membrane Proteins
  • Neoplasm Proteins
  • Thyroid Hormones
  • thyroid hormone-binding proteins
  • Pyruvate Kinase
  • Glutathione