Peroxisome proliferator-activated receptor-γ protects ERBB2-positive breast cancer cells from palmitate toxicity
Open accessAbstract
Introduction: Accumulation of fatty acids and neutral lipids in nonadipose tissues is cytotoxic. We recently showed that ERBB2-positive breast cancer cells produce significantly high amounts of fats, because of overexpression of the peroxisome proliferator-activated receptor (PPAR)γ-binding protein and the nuclear receptor NR1D1 (nuclear receptor subfamily 1, group D, member 1; Rev-erbα). These genes upregulate de novo fatty acid synthesis, which is a critical pathway for the energy production and survival of these cells. NR1D1 and PPARγ-binding protein are functionally related to PPARγ, a well established positive regulator of adipogenesis and lipid storage. Methods: The effects of GW9662 and exogenously added palmitate on breast cells (BT474, MDA-MB-361, MCF-7, and human mammary epithelial cells) in monolayer culture were assessed. Mass spectrometric quantitation of fatty acids and fluorescence-based high content microscopy assays of cell growth, apoptosis, triglyceride storage and reactive oxygen species production were used. Results: ERBB2-positive breast cancer cells are more sensitive to inhibition of PPARγ activity by the antagonist GW9662. PPARγ inhibition results in increased levels of total fats in the cells, mostly because of increased amounts of palmitic and stearic unsaturated acids. Administration of exogenous palmitate is lethal to ERBB2-positive but not to ERBB2-negative cells. GW9662 exacerbates the effects of palmitate addition on BT474 and MDA-MB-361 cells, but it has no significant effect on MCF-7 and human mammary epithelial cells. Palmitate administration results in a fivefold to tenfold greater increase in fat stores in ERBB2-negative cells compared with ERBB2-positive cells, which suggests that the ERBB2-positive cells have maximized their ability to store fats and that additional palmitate is toxic to these cells. Both PPARγ inhibition and palmitate administration result in increased reactive oxygen species production in BT474 cells. The cell death that results from this treatment can be counteracted by the antioxidant N-acetyl cysteine. Conclusions: Our findings indicate that PPARγ activity enables ERBB2-positive breast cancer cells, which produce high levels of fat, to convert fatty acids to triglycerides, allowing these cells to avert the cell death that results from lipotoxicity. Endogenous palmitate toxicity represents a genetically based property of ERBB2-positive breast cancer that can be exploited for therapeutic intervention.
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A concentration of 10 mM GW9662 is commonly used in published scientific studies.
“However, we used GW9662 at a concentration of 10 mM for further experiments because this concentration revealed reproducible results and is a commonly used concentration in published scientific studies (Lea et al., 2004;Kourtidis et al., 2009).”
From The Peroxisome Proliferator–Activated Receptor (PPAR)-γ Antagonist 2-Chloro-5-Nitro-N-Phenylbenzamide (GW9662) Triggers Perilipin 2 Expression via PPARδ and Induces Lipogenesis and Triglyceride Accumulation in Human THP-1 Macrophages (2020) · cites this paper as Kourtidis et al., 2009
The Results (Figure 1; page not provided in our copy) report GW9662 at 10 μmol/l, not 10 mM—a 1,000-fold difference. The paper also does not establish that 10 mM is commonly used. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe higher lipid levels in BT474 cells are primarily caused by an increase in palmitic and stearic acid.
“The higher lipid levels in BT474 cells are primarily caused by an increase in palmitic and stearic acid (Kourtidis et al., 2009).”
From The Peroxisome Proliferator–Activated Receptor (PPAR)-γ Antagonist 2-Chloro-5-Nitro-N-Phenylbenzamide (GW9662) Triggers Perilipin 2 Expression via PPARδ and Induces Lipogenesis and Triglyceride Accumulation in Human THP-1 Macrophages (2020) · cites this paper as Kourtidis et al., 2009
The Results section, “PPARγ inhibition results in increased levels of fats,” says the higher fat levels after PPARγ inhibition were primarily due to increases in palmitic and stearic acids. The citing sentence omits that treatment condition, so the passage does not establish that higher lipid levels in BT474 cells generally have the same explanation. (LLM, conf=0.84)
Experimental — accuracy not yet measuredGW9662 causes triglyceride accumulation in BT474 and MCF-7 cells.
“GW9662 causes triglyceride accumulation in T47D cells (Lea et al., 2004) as well as BT474 and MCF-7 cells (Kourtidis et al., 2009).”
In BT474 and MCF-7 cells, total fat and triglyceride stores were increased by GW9662 treatment.
“In the latter two cell lines, total fat and triglyceride stores were increased by GW9662 treatment.”
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Cites
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“Nevertheless, a number of reports have indicated that the Mediterranean diet, which is rich in the unsaturated oleatecontaining olive oil, has anti-oncogenic properties against ERBB2-positive breast cancer [27,28].”
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Sorted by citations
Schubert, M., Becher, S., Wallert, M., Maeß, M. B., Abhari, M., Rennert, K., Mosig, A. S., Große, S., Heller, R., Grün, M., et al. (2020) · Molecular Pharmacology · doi:10.1124/mol.119.117887 · Cited by 35 · see citing works
- Authors
- Kourtidis, A., Srinivasaiah, R., Carkner, R. D., Brosnan, M. J., & Conklin, D. S.
- Affiliations
- University at Albany, State University of New York (US)
- Corresponding author
- Conklin, Douglas S
- Venue
- Breast Cancer Research
- Published
- 2009-03-19
- Volume
- 11
- Issue
- 2
- Pages
- R16-R16
- ISSN
- 1465-5411 (ISSN-L)
- 1465-542X
- PMC
- PMC2688944
- OpenAlex
- W2016918631
- Cited by
- 60
- References
- 2
- Citations by year
- 2025: 2 · 2024: 1 · 2023: 4 · 2022: 2 · 2021: 3 · 2020: 2 · 2019: 4 · 2018: 5 · 2017: 4 · 2016: 3 · 2015: 4 · 2014: 5 · 2013: 6 · 2012: 4
- FWCI
- 1.68
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Breast Cancer Research (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Dominic Ferraioli Foundation
- U.S. Army Medical Research Acquisition Activity
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- PPARγ, HER2-positive breast cancer, lipotoxicity, fatty acid synthesis, de novo lipogenesis, triglyceride storage, GW9662, reactive oxygen species, apoptosis, N-acetylcysteine, BT474 cells
- MeSH terms
- Breast Neoplasms, Fluorescent Antibody Technique, Humans, Palmitates, RNA, Messenger, Tumor Cells, Cultured, Apoptosis, Reactive Oxygen Species, Receptor, ErbB-2, Erb-b2 Receptor Tyrosine Kinases, Reverse Transcriptase Polymerase Chain Reaction, PPAR gamma, Cell Proliferation
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