AI Article Synopsis

  • Clear cell renal cell carcinoma (ccRCC) is the most prevalent kidney cancer and is often difficult to treat when it spreads, largely due to its lipid accumulation that aids tumor growth and cell survival.
  • Researchers studied two receptors, GPR1 and CMKLR1, that are involved in regulating lipid metabolism in ccRCC; inhibiting these receptors reduced lipid formation and induced cell death in cancer cells, hindering tumor progression.
  • The findings suggest that targeting the CMKLR1 receptor with a specific small molecule could potentially halt tumor growth and lipid storage, offering a new therapeutic strategy for ccRCC treatment.

Article Abstract

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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11290988PMC
http://dx.doi.org/10.1158/0008-5472.CAN-23-2926DOI Listing

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