Building a Foundation for Precision Onco-Nutrition: Docosahexaenoic Acid and Breast Cancer
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Biological Reagents and Chemicals
2.2. Cell Culture and Rationale
2.3. Assessment of Cell Number Accumulation
2.4. Assessment of Cell Proliferation and Apoptosis
2.4.1. Cell Proliferation Assay
2.4.2. Determination of Apoptosis
2.5. Western Blot Analyses
2.6. Statistical Analyses
2.7. OPLS-DA
2.8. Bioinformatic Analyses
3. Results
3.1. DHA Is Superior to EPA in Inhibiting Cancer Cell Growth
3.2. 4-oxo-DHA Exerts Dominant Effects on HER-2/Neu Negative Molecular Subtypes
3.3. 4-oxo-DHA Inhibits Cell Proliferation and Induces Apoptosis
3.4. 4-oxo-DHA Induces the Molecular Signature Indicative of PPARγ Activation
3.5. 4-oxo-DHA Induces Effects on Activity of Proteins in the mTOR Regulatory Network
3.6. Lipid Synthesis Appears to Be a Nexus for cross Talk among Pathways
3.7. Interrogation of Protein Expression Data Using the Ingenuity Pathway Analysis (IPA) Bioinformatics Platform
Regulation of Diseases and Cell Functions
3.8. Regulation of mTOR Signaling
3.9. Analysis Match for Overlap of the 4-oxo-DHA Mediated Signaling in MDAMB-468 with Breast Cancer Treatment Data Sets
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Kapoor, D.; Iqbal, R.; Singh, K.; Jaacks, L.M.; Shivashankar, R.; Sudha, V.; Anjana, R.M.; Kadir, M.; Mohan, V.; Ali, M.K.; et al. Association of dietary patterns and dietary diversity with cardiometabolic disease risk factors among adults in South Asia: The CARRS study. Asia Pac. J. Clin. Nutr. 2018, 27, 1332–1343. [Google Scholar] [CrossRef] [PubMed]
- Department of Health and Human Services National Institutes of Health. 2020–2030 Strategic Plan for NIH Nutrition Research. 2020. Available online: https://www.niddk.nih.gov/about-niddk/strategic-plans-reports/strategic-plan-nih-nutrition-research (accessed on 1 March 2021).
- Otto, M.C.; Padhye, N.S.; Bertoni, A.G.; Jacobs, D.R., Jr.; Mozaffarian, D. Everything in Moderation--Dietary Diversity and Quality, Central Obesity and Risk of Diabetes. PLoS ONE 2015, 10, e0141341. [Google Scholar] [CrossRef] [Green Version]
- Rodgers, G.P.; Collins, F.S. Precision Nutrition-the Answer to “What to Eat to Stay Healthy”. JAMA 2020, 324, 735–736. [Google Scholar] [CrossRef] [PubMed]
- Vadiveloo, M.; Dixon, L.B.; Mijanovich, T.; Elbel, B.; Parekh, N. Dietary variety is inversely associated with body adiposity among US adults using a novel food diversity index. J. Nutr. 2015, 145, 555–563. [Google Scholar] [CrossRef] [Green Version]
- National Research Council. Diet, Nutrition, and Cancer; National Academy Press: Washington, DC, USA, 1982. [Google Scholar]
- Signori, C.; El-Bayoumy, K.; Russo, J.; Thompson, H.J.; Richie, J.P.; Hartman, T.J.; Manni, A. Chemoprevention of breast cancer by fish oil in preclinical models: Trials and tribulations. Cancer Res. 2011, 71, 6091–6096. [Google Scholar] [CrossRef] [Green Version]
- El-Bayoumy, K.; Manni, A. Customized Prevention Trials Could Resolve the Controversy of the Effects of Omega-3 Fatty Acids on Cancer. Nutr. Cancer 2020, 72, 183–186. [Google Scholar] [CrossRef]
- Calder, P.C. Mechanisms of action of (n-3) fatty acids. J. Nutr. 2012, 142, 592s–599s. [Google Scholar] [CrossRef] [Green Version]
- Jiang, W.; Zhu, Z.; McGinley, J.N.; El Bayoumy, K.; Manni, A.; Thompson, H.J. Identification of a Molecular Signature Underlying Inhibition of Mammary Carcinoma Growth by Dietary N-3 Fatty Acids. Cancer Res. 2012, 72, 3795–3806. [Google Scholar] [CrossRef] [Green Version]
- Chen, K.M.; Thompson, H.; Vanden-Heuvel, J.P.; Sun, Y.W.; Trushin, N.; Aliaga, C.; Gowda, K.; Amin, S.; Stanley, B.; Manni, A.; et al. Lipoxygenase catalyzed metabolites derived from docosahexaenoic acid are promising antitumor agents against breast cancer. Sci. Rep. 2021, 11, 410. [Google Scholar] [CrossRef]
- Pogash, T.J.; El-Bayoumy, K.; Amin, S.; Gowda, K.; de Cicco, R.L.; Barton, M.; Su, Y.; Russo, I.H.; Himmelberger, J.A.; Slifker, M.; et al. Oxidized derivative of docosahexaenoic acid preferentially inhibit cell proliferation in triple negative over luminal breast cancer cells. In Vitro Cell. Dev. Biol. Anim. 2015, 51, 121–127. [Google Scholar] [CrossRef] [Green Version]
- McGahon, A.J.; Martin, S.J.; Bissonnette, R.P.; Mahboubi, A.; Shi, Y.; Mogil, R.J.; Nishioka, W.K.; Green, D.R. Chapter 9 the End of the (Cell) Line: Methods for the Study of Apoptosis in Vitro. In Methods in Cell Biology; Schwartz, L.M., Osborne, B.A., Eds.; Academic Press: Cambridge, MA, USA, 1995; Volume 46, pp. 153–185. [Google Scholar]
- Zhu, Z.; Jiang, W.; Thompson, M.D.; McGinley, J.N.; Thompson, H.J. Metformin as an energy restriction mimetic agent for breast cancer prevention. J. Carcinog 2011, 10, 17. [Google Scholar]
- Li, J.; Zheng, Z.; Liu, M.; Ren, Y.; Ruan, Y.; Li, D. Relationship between the n-3 index, serum metabolites and breast cancer risk. Food Funct. 2021, 12, 7741–7748. [Google Scholar] [CrossRef]
- Molfino, A.; Amabile, M.I.; Lionetto, L.; Spagnoli, A.; Ramaccini, C.; De Luca, A.; Simmaco, M.; Monti, M.; Muscaritoli, M. DHA Oral Supplementation Modulates Serum Epoxydocosapentaenoic Acid (EDP) Levels in Breast Cancer Patients. Oxid. Med. Cell. Longev. 2019, 2019, 1280987. [Google Scholar] [CrossRef]
- Schmocker, C.; Zhang, I.W.; Kiesler, S.; Kassner, U.; Ostermann, A.I.; Steinhagen-Thiessen, E.; Schebb, N.H.; Weylandt, K.H. Effect of Omega-3 Fatty Acid Supplementation on Oxylipins in a Routine Clinical Setting. Int. J. Mol. Sci. 2018, 19, 180. [Google Scholar] [CrossRef] [Green Version]
- Buchanan, P.J.; Gilman, R.H. Retinoids: Literature Review and Suggested Algorithm for Use Prior to Facial Resurfacing Procedures. J. Cutan. Aesthet. Surg. 2016, 9, 139–144. [Google Scholar] [CrossRef]
- Maestro, M.A.; Molnár, F.; Carlberg, C. Vitamin D and Its Synthetic Analogs. J. Med. Chem. 2019, 62, 6854–6875. [Google Scholar] [CrossRef] [PubMed]
- Picklo, M.; Marcotte, B.V.; Bukowski, M.; Toro-Martín, J.D.; Rust, B.M.; Guénard, F.; Vohl, M.C. Identification of Phenotypic Lipidomic Signatures in Response to Long Chain n-3 Polyunsaturated Fatty Acid Supplementation in Humans. J. Am. Heart Assoc. 2021, 10, e018126. [Google Scholar] [CrossRef]
- Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell 2011, 144, 646–674. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Signori, C.; DuBrock, C.; Richie, J.P.; Prokopczyk, B.; Demers, L.M.; Hamilton, C.; Hartman, T.J.; Liao, J.; El-Bayoumy, K.; Manni, A. Administration of omega-3 fatty acids and Raloxifene to women at high risk of breast cancer: Interim feasibility and biomarkers analysis from a clinical trial. Eur. J. Clin. Nutr. 2012, 66, 878–884. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pizato, N.; Hoffmann, M.S.; Irala, C.H.; Muniz-Junqueira, M.I.; Silva Paixao, E.M.D.; Ito, M.K. Serum fatty acid synthase levels and n-3 fatty acid intake in patients with breast cancer. Clin. Nutr. ESPEN 2021, 42, 142–147. [Google Scholar] [CrossRef]
- Newell, M.; Mazurak, V.; Postovit, L.M.; Field, C.J. N-3 Long-Chain Polyunsaturated Fatty Acids, Eicosapentaenoic and Docosahexaenoic Acid, and the Role of Supplementation during Cancer Treatment: A Scoping Review of Current Clinical Evidence. Cancers 2021, 13, 1206. [Google Scholar] [CrossRef] [PubMed]
- Su, M.; Mei, Y.; Sinha, S. Role of the Crosstalk between Autophagy and Apoptosis in Cancer. J. Oncol. 2013, 2013, 102735. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wang, T.T.; Yang, Y.; Wang, F.; Yang, W.G.; Zhang, J.J.; Zou, Z.Q. Docosahexaenoic acid monoglyceride induces apoptosis and autophagy in breast cancer cells via lipid peroxidation-mediated endoplasmic reticulum stress. J. Food Sci. 2021, 86, 4704–4716. [Google Scholar] [CrossRef] [PubMed]
- Kosgei, V.J.; Coelho, D.; Gueant-Rodriguez, R.M.; Gueant, J.L. Sirt1-PPARS Cross-Talk in Complex Metabolic Diseases and Inherited Disorders of the One Carbon Metabolism. Cells 2020, 9, 1882. [Google Scholar] [CrossRef] [PubMed]
Cell Lines | BT474 | SKBR-3 | MDAMB468 | |||
---|---|---|---|---|---|---|
ER | + | - | - | |||
PR | + | - | - | |||
HER2 | + | + | - | |||
4-oxo-DHA (µM) | 0 | 25 | 0 | 25 | 0 | 25 |
Cell proliferation | ||||||
Index (OD) | 0.24 ± 0.01 | 0.23 ± 0.01 * | 0.56 ± 0.01 | 0.50 ± 0.01 * | 0.45 ± 0.01 | 0.37 ± 0.01 * |
RbSer780 ratio | 1.16 ± 0.08 | 0.45 ± 0.01* | 0.83 ± 0.03 | 0.70 ± 0.02 * | 3.21 ± 0.10 | 2.22 ± 0.07 * |
Cyclin D1 | 2703 ± 66 | 2201 ± 42 * | 2666 ± 185 | 2643 ± 142 | 2494 ± 50 | 1895 ± 60 * |
P21 | 24.0 ± 0.9 | 34.4 ± 2.9 * | 30.3 ± 3.6 | 45.4 ± 1.3 * | 49.9 ± 1.6 | 63.4 ± 2.9 * |
P27 | 45.5 ± 2.2 | 84.3 ± 3.8 * | 17.1 ± 1.5 | 29.7 ± 1.8 * | 44.0 ± 2.5 | 52.9 ± 1.4 * |
Apoptosis | ||||||
Index (%) | 3.0 ± 0.1 | 25.1 ± 0.5 * | 3.1 ± 0.2 | 18.8 ± 0.5 * | 3.0 ± 0.1 | 14.6 ± 0.3 * |
Apaf-1 | 190 ± 6 | 183 ± 4 | 255 ± 9 | 304 ± 15 * | 529 ± 7 | 521 ± 10 |
Bax | 49.9 ± 1.8 | 32.5 ± 0.6 * | 92.8 ± 5.1 | 130 ± 7 * | 220 ± 15 | 248 ± 15 |
Bcl-2 | 231 ± 12 | 99.5 ± 2.7 * | 47.8 ± 2.2 | 38.3 ± 3.7 * | 538 ± 14 | 367 ± 23 * |
Bax/Bcl-2 | 0.22 ± 0.01 | 0.33 ± 0.01 * | 1.95 ± 0.06 | 3.62 ± 0.44 * | 0.41 ± 0.04 | 0.68 ± 0.02 * |
PARP89 | 63.3 ± 4.6 | 28.9 ± 1.1 * | 51.6 ± 2.9 | 44.1 ± 6.5 | 84.0 ± 1.5 | 88.1 ± 2.4 |
PARP116 | 1225 ± 16 | 407 ± 5 * | 1614 ± 40 | 1301 ± 132 | 1215 ± 25 | 973 ± 39 * |
PARP89/116 | 0.05 ± 0.01 | 0.07 ± 0.01 * | 0.03 ± 0.01 | 0.03 ± 0.01 | 0.07 ± 0.01 | 0.09 ± 0.01* |
Cell Lines | BT474 | SKBR3 | MDAMB468 | |||
---|---|---|---|---|---|---|
ER | + | - | - | |||
PR | + | - | - | |||
HER2 | + | + | - | |||
4-oxo-DHA (µM) | 0 | 25 | 0 | 25 | 0 | 25 |
PPARβ | 153 ± 3 | 86 ± 2 * | 130 ± 5 | 110 ± 2 * | 198 ± 10 | 215 ± 8 |
PPARγ | 45 ± 1 | 57 ± 1 * | 94 ± 2 | 124 ± 3 * | 126 ± 1 | 153 ± 2 * |
GPR120 | 13.1 ± 0.3 | 22.6 ± 0.8 * | 25.3 ± 1.1 | 25.5 ± 1.5 | 31.6 ± 1.1 | 41.8 ± 3.6 * |
Hif-1α | 179 ± 8 | 96 ± 4 * | 398 ± 20 | 434 ± 48 | 468 ± 30 | 319 ± 35 * |
SIRT-1 | 663 ± 18 | 304 ± 5 * | 1228 ± 85 | 1266 ± 72 | 1021 ± 41 | 927 ± 34 |
GADD153 | 87 ± 3 | 43 ± 2 * | 209 ± 23 | 274 ± 407 | 432 ± 28 | 338 ± 10 * |
Ratios | ||||||
NF-κB p65Ser536 | 0.65 ± 0.04 | 0.45 ± 0.03 * | 0.45 ± 0.02 | 0.50 ± 0.02 | 2.38 ± 0.12 | 1.28 ± 0.08 * |
FOXO3aThr32 | 3.32 ± 0.04 | 0.94 ± 0.19 * | 1.92 ± 0.18 | 0.80 ± 0.11 * | 5.97 ± 0.06 | 5.25 ± 0.09 * |
Cell Lines | BT474 | SKBR3 | MDAMB468 | |||
---|---|---|---|---|---|---|
ER | + | - | - | |||
PR | + | - | - | |||
HER2 | + | + | - | |||
4-oxo-DHA (µM) | 0 | 25 | 0 | 25 | 0 | 25 |
IGF-1R | 80 ± 5 | 38 ± 2 * | 61 ± 4 | 50 ± 1 * | 296 ± 3 | 236 ± 2 * |
PI3Kp110 | 174 ± 5 | 129 ± 3 * | 294 ± 16 | 228 ± 16 * | 192 ± 1 | 158 ± 3 * |
Ratios | ||||||
IRS1Ser636/639 | 0.52 ± 0.02 | 0.27 ± 0.01 * | 0.77 ± 0.05 | 0.79 ± 0.06 | 0.60 ± 0.02 | 0.59 ± 0.02 |
AMPKThr172 | 0.06 ± 0.01 | 0.25 ± 0.01 * | 0.07 ± 0.01 | 0.12 ± 0.01 * | 0.08 ± 0.01 | 0.11 ± 0.01 * |
AktSer473 | 3.29 ± 0.13 | 0.78 ± 0.03 * | 3.23 ± 0.23 | 1.01 ± 0.08 * | 7.68 ± 0.29 | 6.50 ± 0.26 * |
mTORSer2448 | 0.61 ± 0.02 | 0.23 ± 0.01 * | 0.17 ± 0.01 | 0.16 ± 0.01 | 0.25 ± 0.02 | 0.20 ± 0.01 * |
RaptorSer792 | 0.08 ± 0.01 | 0.15 ± 0.01 * | 0.05 ± 0.01 | 0.06 ± 0.01 | 0.08 ± 0.01 | 0.10 ± 0.01 * |
PRAS40Thr246 | 2.79 ± 0.08 | 1.80 ± 0.07 * | 1.43 ± 0.06 | 1.26 ± 0.03 | 2.47 ± 0.06 | 2.05 ± 0.01 * |
P70S6KThr389 | 0.26 ± 0.01 | 0.10 ± 0.01 * | 0.55 ± 0.17 | 0.10 ± 0.01 * | 0.93 ± 0.03 | 0.67 ± 0.03 * |
4E-BP1Thr37/46 | 1.30 ± 0.09 | 0.88 ± 0.03 * | 1.62 ± 0.27 | 1.39 ± 0.16 | 0.89 ± 0.04 | 0.65 ± 0.02 * |
Cell Lines | BT474 | SKBR-3 | MDAMB-468 | |||
---|---|---|---|---|---|---|
ER | + | - | - | |||
PR | + | - | - | |||
HER2 | + | + | - | |||
4-oxo-DHA (µM) | 0 | 25 | 0 | 25 | 0 | 25 |
FASN | 787 ± 22 | 552 ± 3 * | 2081 ± 86 | 2150 ± 34 | 1141 ± 82 | 1132 ± 74 |
HMGCR | 469 ± 8 | 396 ± 9 * | 275 ± 22 | 309 ± 33 | 566 ± 20 | 432 ± 42 * |
SREBP-1 | 297 ± 11 | 123 ± 3 * | 568 ± 25 | 399 ± 8 * | 575 ± 17 | 520 ± 28 |
ACCSer79 ratio | 0.36 ± 0.03 | 0.75 ± 0.08 * | 0.28 ± 0.03 | 1.13 ± 0.35 * | 0.83 ± 0.02 | 1.07 ± 0.04 * |
Target Gene 1 | Treatment 2 | Z-Score 3 | Accession ID |
---|---|---|---|
mTOR | AZD8055 | 23.88 | GSE70138 |
multiple targets | Celastrol | 16.15 | GSE70138 |
CDK1; 2 | CGP60474 | 15.67 | GSE70138 |
CDK | AT7519 | 14.17 | GSE70138 |
CDK | AZD5438 | 13.36 | GSE70138 |
CDK9 | Alvocidib | 14.17 | GSE70138 |
JNKs | CC401 | 15.67 | GSE70138 |
MEK | AZD8330 | 14.94 | GSE70138 |
IKKbeta; alpha 2 | BMS345541 | 14.17 | GSE70138 |
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Thompson, H.J.; Neil, E.S.; McGinley, J.N.; Fitzgerald, V.K.; El Bayoumy, K.; Manni, A. Building a Foundation for Precision Onco-Nutrition: Docosahexaenoic Acid and Breast Cancer. Cancers 2022, 14, 157. https://doi.org/10.3390/cancers14010157
Thompson HJ, Neil ES, McGinley JN, Fitzgerald VK, El Bayoumy K, Manni A. Building a Foundation for Precision Onco-Nutrition: Docosahexaenoic Acid and Breast Cancer. Cancers. 2022; 14(1):157. https://doi.org/10.3390/cancers14010157
Chicago/Turabian StyleThompson, Henry J., Elizabeth S. Neil, John N. McGinley, Vanessa K. Fitzgerald, Karam El Bayoumy, and Andrea Manni. 2022. "Building a Foundation for Precision Onco-Nutrition: Docosahexaenoic Acid and Breast Cancer" Cancers 14, no. 1: 157. https://doi.org/10.3390/cancers14010157