GCN2 eIF2 kinase promotes prostate cancer by maintaining amino acid homeostasis
- Indiana University, United States
- Rutgers, The State University of New Jersey, United States
- Purdue University West Lafayette, United States
- Indiana University School of Medicine, United States
- University at Buffalo, State University of New York, United States
Abstract
A stress adaptation pathway termed the integrated stress response has been suggested to be active in many cancers including prostate cancer (PCa). Here, we demonstrate that the eIF2 kinase GCN2 is required for sustained growth in androgen-sensitive and castration-resistant models of PCa both in vitro and in vivo, and is active in PCa patient samples. Using RNA-seq transcriptome analysis and a CRISPR-based phenotypic screen, GCN2 was shown to regulate expression of over 60 solute-carrier (SLC) genes, including those involved in amino acid transport and loss of GCN2 function reduces amino acid import and levels. Addition of essential amino acids or expression of 4F2 (SLC3A2) partially restored growth following loss of GCN2, suggesting that GCN2 targeting of SLC transporters is required for amino acid homeostasis needed to sustain tumor growth. A small molecule inhibitor of GCN2 showed robust in vivo efficacy in androgen-sensitive and castration-resistant mouse models of PCa, supporting its therapeutic potential for the treatment of PCa.
Data availability
The authors declare that all data generated or analyzed in this study are included in the published article, its supplementary information and source files, or are publicly available. The CHARGE-seq and RNA-seq datasets generated in this study have been deposited in the NCBI Gene Expression Omnibus (GEO) database under the ascension codes GSE196251 and GSE196252, respectively. The custom python script used in the analysis of our Charge-seq study is available on GitHub (https://github.com/carlsonkPhD/tRNA_Charge-Seq/). Gene expression data from prostate cancer patients (PRAD) in the TCGA database used for correlation analysis is publicly available.
-
GCN2 eIF2 kinase promotes prostate cancer by maintaining amino acid homeostasisNCBI Gene Expression Omnibus, GSE196251.
-
GCN2 eIF2 kinase promotes prostate cancer by maintaining amino acid homeostasisNCBI Gene Expression Omnibus, GSE196252.
Article and author information
Author details
Funding
NIH Office of the Director (GM136331)
- Ronald C Wek
NIH Office of the Director (DK109714)
- Tracy G Anthony
National Cancer Institute (R21CA221942)
- Robero Pili
Indiana University Melvin and Bren Simon Comprehensive Cancer Center (P30CA082709)
- Kirk A Staschke
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal experiments were approved by the Institutional Animal Care and Use Committee (IACUC) at Indiana University School of Medicine (Protocol #21014) and comply with all regulations for ethical conduct of animal research. Human prostate core needle biopsy specimens were obtained from the Indiana University Comprehensive Cancer Center Tissue Procurement and Distribution Core and approval was granted by the Institutional Review Board (IRB #1796) at the Office of Research Administration at Indiana University.
Copyright
© 2022, Cordova et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 3,691
- views
-
- 774
- downloads
-
- 23
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
GCN2 eIF2 kinase promotes prostate cancer by maintaining amino acid homeostasis
eLife 11:e81083.
https://doi.org/10.7554/eLife.81083
Further reading
-
- Cancer Biology
Metastasis is the leading cause of cancer-related mortality. Paneth cells provide stem cell niche factors in homeostatic conditions, but the underlying mechanisms of cancer stem cell niche development are unclear. Here, we report that Dickkopf-2 (DKK2) is essential for the generation of cancer cells with Paneth cell properties during colon cancer metastasis. Splenic injection of Dkk2 knockout (KO) cancer organoids into C57BL/6 mice resulted in a significant reduction of liver metastases. Transcriptome analysis showed reduction of Paneth cell markers such as lysozymes in KO organoids. Single-cell RNA sequencing analyses of murine metastasized colon cancer cells and patient samples identified the presence of lysozyme positive cells with Paneth cell properties including enhanced glycolysis. Further analyses of transcriptome and chromatin accessibility suggested hepatocyte nuclear factor 4 alpha (HNF4A) as a downstream target of DKK2. Chromatin immunoprecipitation followed by sequencing analysis revealed that HNF4A binds to the promoter region of Sox9, a well-known transcription factor for Paneth cell differentiation. In the liver metastatic foci, DKK2 knockout rescued HNF4A protein levels followed by reduction of lysozyme positive cancer cells. Taken together, DKK2-mediated reduction of HNF4A protein promotes the generation of lysozyme positive cancer cells with Paneth cell properties in the metastasized colon cancers.
-
- Cancer Biology
A high density of tumor-associated macrophages (TAMs) is associated with poorer prognosis and survival in breast cancer patients. Recent studies have shown that lipid accumulation in TAMs can promote tumor growth and metastasis in various models. However, the specific molecular mechanisms that drive lipid accumulation and tumor progression in TAMs remain largely unknown. Herein, we demonstrated that unsaturated fatty acids (FAs), unlike saturated ones, are more likely to form lipid droplets in murine macrophages. Specifically, unsaturated FAs, including linoleic acids (LA), activate the FABP4/CEBPα pathway, leading to triglyceride synthesis and lipid droplet formation. Furthermore, FABP4 enhances lipolysis and FA utilization by breast cancer cell lines, which promotes cancer cell migration in vitro and metastasis in vivo. Notably, a deficiency of FABP4 in murine macrophages significantly reduces LA-induced lipid metabolism. Therefore, our findings suggest FABP4 as a crucial lipid messenger that facilitates unsaturated FA-mediated lipid accumulation and lipolysis in TAMs, thus contributing to the metastasis of breast cancer.
