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PKLR promotes colorectal cancer liver colonization through induction of glutathione synthesis
Alexander Nguyen, … , Elisa de Stanchina, Sohail F. Tavazoie
Alexander Nguyen, … , Elisa de Stanchina, Sohail F. Tavazoie
Published January 19, 2016
Citation Information: J Clin Invest. 2016;126(2):681-694. https://doi.org/10.1172/JCI83587.
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Research Article Oncology Article has an altmetric score of 2

PKLR promotes colorectal cancer liver colonization through induction of glutathione synthesis

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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.

Authors

Alexander Nguyen, Jia Min Loo, Rohit Mital, Ethan M. Weinberg, Fung Ying Man, Zhaoshi Zeng, Philip B. Paty, Leonard Saltz, Yelena Y. Janjigian, Elisa de Stanchina, Sohail F. Tavazoie

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Figure 4

PKLR promotes metastatic cell survival in the tumor core.

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PKLR promotes metastatic cell survival in the tumor core.
(A) 5 × 105 SW...
(A) 5 × 105 SW620 cells were inoculated by portal circulation injection, and apoptotic cell burden in the liver was monitored using DEVD-luciferin bioluminescence relative to live cell bioluminescence over time (n = 5). *P < 0.05, **P < 0.01, 1-sided t test between indicated sample and shControl. (B) Cumulative apoptotic/live cell burden over time was determined by calculating the area under the curve for each mouse. Linear regression lines are shown. ***P < 0.001, ANCOVA testing for difference in slope between indicated sample and shControl. (C) Livers were extracted in the previous experiment after 28 days, and nodules per liver section were quantified (n = 4). The average value from 3 liver sections for each mouse was used. *P < 0.05, 1-sided t test between indicated sample and shControl. (D) For each liver, proportion of the indicated nodule type is shown. ***P < 0.001, 2-sided Fisher’s exact test on total nodule count for each PKLR shRNA compared with shControl. (E) Representative images of nodule types. DAPI (blue) was used to label nuclei, cleaved caspase-3 (red) was used to label apoptosis, and luciferase and human vimentin (green) were used to label cancer cells. Scale bar: 50 μm.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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