PKLR promotes colorectal cancer liver colonization through induction of glutathione synthesis Journal Article

   

Authors:	Nguyen, A.; Loo, J. M.; Mital, R.; Weinberg, E. M.; Man, F. Y.; Zeng, Z.; Paty, P. B.; Saltz, L.; Janjigian, Y. Y.; De Stanchina, E.; Tavazoie, S. F.
Article Title:	PKLR promotes colorectal cancer liver colonization through induction of glutathione synthesis
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.
Journal Title:	Journal of Clinical Investigation
Volume:	126
Issue:	2
ISSN:	0021-9738
Publisher:	American Society for Clinical Investigation
Date Published:	2016-02-01
Start Page:	681
End Page:	694
Language:	English
DOI:	10.1172/jci83587
PROVIDER:	scopus
PMCID:	PMC4731165
PUBMED:	26784545
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84956961637&partnerID=40&md5=e6c2dc8e34a7d274d12a7bde3efffb4e
Notes:	Article -- Export Date: 3 March 2016 -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/89313