Journal article
ANGPTL4 suppresses clear cell renal cell carcinoma via inhibition of lysosomal acid lipase
Cancer research communications, Vol.4(8), pp.2242-2254
08/2024
DOI: 10.1158/2767-9764.CRC-24-0016
PMCID: PMC11348483
PMID: 39105498
Abstract
Abstract Renal cell carcinoma (RCC), the most common form of kidney cancer, is a heterogeneous disease with clear cell RCC (ccRCC) being the most prevalent and aggressive subtype. While most ccRCC tumors have elevated expression of angiopoietin-like 4 (ANGPTL4), in our study we identified a significant subset of patients whose cancers show no increase in ANGPTL4 expression. These patients have a worse prognosis compared to the patients with high expression of ANGPTL4. These ANGPTL4-low cancers are characterized by the increased frequency of wild-type Von Hippel-Lindau (wt VHL), a gene that is commonly mutated in ccRCC, and an enrichment for genes associated with lipid metabolism. Using RCC tumor models with wild type VHL, we demonstrate that ANGPTL4 behaves as a tumor suppressor. The loss of ANGPTL4 in ccRCC cell lines results in increased tumor growth and colony formation in a lysosomal acid lipase (LAL)-dependent manner, a phenotype rescued by the expression of N-terminus ANGPTL4. At the mechanistic level, the loss of ANGPTL4 increases lysosomal acid lipase activity in ccRCC cells. This data suggests that ANGPTL4 enacts its tumor-suppressive effects in ccRCC by regulating LAL activity. Importantly, the identified patient cohort with low ANGPTL4 expression may exhibit increased reliance on lipid metabolism, which can be a point of target for future therapy.
Details
- Title: Subtitle
- ANGPTL4 suppresses clear cell renal cell carcinoma via inhibition of lysosomal acid lipase
- Creators
- Zeng Jin - University of FloridaUmasankar De - University of FloridaTanzia Islam Tithi - University of FloridaJeremy Kleberg - University of FloridaAkhila Nataraj - University of FloridaElena Jolley - University of FloridaMadison E Carelock - University of FloridaBrandon S Davies - University of IowaWeizhou Zhang - University of FloridaRyan Kolb - University of Florida
- Resource Type
- Journal article
- Publication Details
- Cancer research communications, Vol.4(8), pp.2242-2254
- DOI
- 10.1158/2767-9764.CRC-24-0016
- PMID
- 39105498
- PMCID
- PMC11348483
- NLM abbreviation
- Cancer Res Commun
- ISSN
- 2767-9764
- eISSN
- 2767-9764
- Publisher
- AMER ASSOC CANCER RESEARCH
- Grant note
- NIH: K22 CA229595, R01CA260239, R01CA269661
This project was supported by the NIH K22 CA229595 (R. Kolb), NIH R01CA260239 (W. Zhang), NIH R01CA269661 (W. Zhang), start-up funds from the Department of Pathology, Immunology and Laboratory Medicine at the University of Florida, the University of Florida Health Cancer Center and the University of Florida College of Medicine (R. Kolb and W. Zhang), and an endowment from the James Robert Spencer Family Cancer Research Fund (W. Zhang).
- Language
- English
- Electronic publication date
- 08/06/2024
- Date published
- 08/2024
- Academic Unit
- Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology
- Record Identifier
- 9984695559702771
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