GPR1 and CMKLR1 Control Lipid Metabolism to Support the Development of Clear Cell Renal Cell Carcinoma.

Autor:	Wang D; Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida.; Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, Florida., Mahmud I; Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, Texas., Thakur VS; Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida., Tan SK; Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida., Isom DG; Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida.; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida., Lombard DB; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida.; Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, Florida.; Bruce W. Carter VAMC, Miami, Florida., Gonzalgo ML; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida.; Desai Sethi Urology Institute, University of Miami Miller School of Medicine, Miami, Florida., Kryvenko ON; Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida.; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida.; Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, Florida.; Desai Sethi Urology Institute, University of Miami Miller School of Medicine, Miami, Florida., Lorenzi PL; Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, Texas., Tcheuyap VT; Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas., Brugarolas J; Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas.; Department of Internal Medicine/Hematology-Oncology, The University of Texas Southwestern Medical Center, Dallas, Texas., Welford SM; Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida.; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2024 Jul 02; Vol. 84 (13), pp. 2141-2154.
DOI:	10.1158/0008-5472.CAN-23-2926
Abstrakt:	Clear cell renal cell carcinoma (ccRCC), the most common type of kidney cancer, is largely incurable in the metastatic setting. ccRCC is characterized by excessive lipid accumulation that protects cells from stress and promotes tumor growth, suggesting that the underlying regulators of lipid storage could represent potential therapeutic targets. Here, we evaluated the regulatory roles of GPR1 and CMKLR1, two G protein-coupled receptors of the protumorigenic adipokine chemerin that is involved in ccRCC lipid metabolism. Both genetic and pharmacologic suppression of either receptor suppressed lipid formation and induced multiple forms of cell death, including apoptosis, ferroptosis, and autophagy, thereby significantly impeding ccRCC growth in cell lines and patient-derived xenograft models. Comprehensive lipidomic and transcriptomic profiling of receptor competent and depleted cells revealed overlapping and unique signaling of the receptors granting control over triglyceride synthesis, ceramide production, and fatty acid saturation and class production. Mechanistically, both receptors enforced suppression of adipose triglyceride lipase, but each receptor also demonstrated distinct functions, such as the unique ability of CMKLR1 to control lipid uptake through regulation of sterol regulatory element-binding protein 1c and the CD36 scavenger receptor. Treating patient-derived xenograft models with the CMKLR1-targeting small molecule 2-(α-naphthoyl) ethyltrimethylammonium iodide (α-NETA) led to a dramatic reduction in tumor growth, lipid storage, and clear-cell morphology. Together, these findings provide mechanistic insights into lipid regulation in ccRCC and identify a targetable axis at the core of the histologic definition of this tumor that could be exploited therapeutically. Significance: Extracellular control of lipid accumulation via G protein receptor-mediated cell signaling is a metabolic vulnerability in clear cell renal cell carcinoma, which depends on lipid storage to avoid oxidative toxicity. (©2024 American Association for Cancer Research.)
Databáze:	MEDLINE
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