Obesity-Dependent Adipokine Chemerin Suppresses Fatty Acid Oxidation to Confer Ferroptosis Resistance

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. See related commentary by Reznik et al., p. 1879. This article is highlighted in the In This Issue feature, p. 1861

Adipogenic Transdifferentiation and Regulatory Factors Promote the Progression and the Immunotherapy Response of Renal Cell Carcinoma: Insights From Integrative Analysis

“…In the current study, we first verified that the distribution of adipokine chemerin promoting cellular adiposity differentiation differed significantly between clinical subgroups, and that the gene RARRES2 was expressed more in the advanced subgroups. This demonstrated a positive correlation between the degree of tumor cell adipogenic transdifferentiation and the severity of the disease, which was consistent with the previous findings ( 8 ). Next, based on extracted 49 differentially expressed genes from genes encoding specific proteins secreted by adipocytes, we defined two subtypes with distinct clinical and biological features in ccRCC.…”

“…assessed the expression of adipokines in ccRCC and discovered the adipokine chemerin, which was encoded by the retinoic acid receptor responder 2 (RARRES2) gene ( 8 ). The functions of this chemerin were verified as inhibiting fatty acid oxidation, maintaining intracellular fatty acid levels, preventing ferroptosis, and promoting cellular adipogenic transdifferentiation ( 8 , 9 ). Their research data suggested that obesity and tumor cells would promote the occurrence of ccRCC through the adipokine chemerin.…”

Medulloblastoma cerebrospinal fluid reveals metabolites and lipids indicative of hypoxia and cancer-specific RNAs

“…Global metabolomics has become an important unbiased approach to identify diagnostic, prognostic, and predictive biomarkers in human disease [17,52], and altered metabolism is a hallmark of cancer cells, which need to adapt to their nutrient-poor microenvironment to sustain their viability [53]. Although it is clear that cancer cells have altered metabolism, it is less clear to what extent this influences the CNS microenvironment and the CSF.…”

The Role of Iron in Cancer Progression

“…There are also some new discoveries focusing on the relationship between lipid peroxidation and ferroptosis. Tan et al found a hypoxia-inducible factor-dependent adipokine chemerin, which could prevent fatty acid oxidation and lead to escape from ferroptosis, and targeting chemerin reduced lipid storage and tumor growth (137); Lang et al demonstrated that supplementing unsaturated fatty acids while inhibiting the biogenesis of lipid droplets could induce ferroptosis in acidic cancer cells (138); Additionally, Dierge et al found that a diet rich in n-3 long-chain unsaturated fatty acids significantly i n h ib i t ed tu m o r g r o w t h in m i c e , i n d i c a t i ng t h a t supplementation of dietary unsaturated fatty acids can serve as a selective adjuvant anti-tumor approach (139); Furthermore, supplementation of dietary unsaturated fatty acids may serve as a selective adjuvant anti-tumor approach. W. Liu et al verified that dyslipidemia affected the occurrence and development of tumors by selectively resisting ferroptosis, which primarily due to the continued expression of GPX4 in the metabolism of 27hydroxycholesterol-resistant cells (140); In consistent, Beatty et al identified conjugated linoleic acids, including aeleostearic acid (aESA), acted as inducers of ferroptosisby acyl coenzyme a synthetase long-chain isomer 1 and interfering with the biosynthesis of triglycerides inhibited aESA-induced ferroptosis, but not GPX4-inhibited ferroptosis (141).…”

“…Tan et al. found a hypoxia-inducible factor-dependent adipokine chemerin, which could prevent fatty acid oxidation and lead to escape from ferroptosis, and targeting chemerin reduced lipid storage and tumor growth ( 137 ); Lang et al. demonstrated that supplementing unsaturated fatty acids while inhibiting the biogenesis of lipid droplets could induce ferroptosis in acidic cancer cells ( 138 ); Additionally, Dierge et al.…”