Obesity-dependent adipokine chemerin suppresses fatty acid oxidation to confer ferroptosis resistance

Sze Kiat Tan, Iqbal Mahmud, Flavia Fontanesi, Michelle Puchowicz, Chase K.A. Neumann, Anthony J. Griswold, Rutulkumar Patel, Marco Dispagna, Hamzah H. Ahmed, Mark L. Gonzalgo, J. Mark Brown, Timothy J. Garrett, Scott M. Welford

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Clear cell renal cell carcinoma (ccRCC) is characterized by accumulation of neutral lipids and adipogenic transdifferentiation. We assessed adipokine expression in ccRCC and found that tumor tissues and patient plasma exhibit obesity-dependent elevations of the adipokine chemerin. Attenuation of chemerin by several approaches led to significant reduction in lipid deposition and impairment of tumor cell growth in vitro and in vivo. A multi-omics approach revealed that chemerin suppresses fatty acid oxidation, preventing ferroptosis, and maintains fatty acid levels that activate hypoxia-inducible factor 2α expression. The lipid coenzyme Q and mitochondrial complex IV, whose biogeneses are lipid-dependent, were found to be decreased after chemerin inhibition, contributing to lipid reactive oxygen species production. Monoclonal antibody targeting chemerin led to reduced lipid storage and diminished tumor growth, demonstrating translational potential of chemerin inhibition. Collectively, the results suggest that obesity and tumor cells contribute to ccRCC through the expression of chemerin, which is indispensable in ccRCC biology. Significance: Identification of a hypoxia-inducible factor–dependent adipokine that prevents fatty acid oxidation and causes escape from ferroptosis highlights a critical metabolic dependency unique in the clear cell subtype of kidney cancer. Targeting lipid metabolism via inhibition of a soluble factor is a promising pharmacologic approach to expand therapeutic strategies for patients with ccRCC.

Original languageEnglish (US)
Pages (from-to)2072-2093
Number of pages22
JournalCancer discovery
Volume11
Issue number8
DOIs
StatePublished - Aug 2021

ASJC Scopus subject areas

  • Oncology

Fingerprint

Dive into the research topics of 'Obesity-dependent adipokine chemerin suppresses fatty acid oxidation to confer ferroptosis resistance'. Together they form a unique fingerprint.

Cite this