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Background: This study examined the effects of flaxseed oil supplementation on the expression of adenosine monophosphate-activated protein kinase alpha2 (AMPKα2) in male patients with follicular thyroid cancer. The objective was to assess whether flaxseed oil could enhance AMPKα2 activity, improve histological features, and reduce tumor cell viability, offering a potential therapeutic benefit for diabetic and non-diabetic patients.
Results: A total of 303 patients, including 149 non-diabetic and 154 diabetic participants, received 1250 mg of flaxseed oil daily for one month. Flaxseed oil supplementation significantly improved tumor histology, with treated tissues showing organized follicular patterns and reduced fibrovascular cells compared to untreated tissues. Cell viability assays demonstrated a dose-dependent reduction in papillary thyroid carcinoma cell viability, with the strongest effects observed at flaxseed extract concentrations of 80, 50, and 30 µg/mL. Molecular analyses revealed increased AMPKα2 expression in both treated thyroid cancer tissues and cell line models, indicating enhanced protein activation. These findings suggest that flaxseed oil supplementation may inhibit tumor proliferation and improve histological organization in follicular thyroid cancer.
Conclusions: Flaxseed oil supplementation activates AMPKα2, reduces tumor cell viability, and improves histopathological features in follicular thyroid cancer tissues. These results highlight the potential of flaxseed oil as an adjunctive therapy to enhance cancer management strategies, particularly in diabetic and non-diabetic patients with follicular thyroid cancer.
References
Daniels GH. Follicular thyroid carcinoma: a perspective. Thyroid 2018;28(10):1229-42. https://doi.org/10.1089/thy.2018.0306 PMid: 30039751
Kari S, Vasko VV, Priya S, et al. PKA activates AMPK through LKB1 signaling in follicular thyroid cancer. Front Endocrinol 2019;10:769-79. https://doi.org/10.3389/fendo.2019.00769 PMid: 31798532
Pringle DR, Vasko VV, Yu L, et al. Follicular thyroid cancers demonstrate dual activation of PKA and mTOR as modeled by thyroid-specific deletion of Prkar1a and Pten in mice. J Clin Endocrinol Metab 2014;99:804-12. https://doi.org/10.1210/jc.2013-3101 PMid: 24512487
Jeon SM, Chandel NS, Hay N. AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature. 2012;485:661-5. https://doi.org/10.1038/nature11066 PMid: 22660331
Andrade BM, de Carvalho DP. Perspectives of the AMP-activated kinase (AMPK) signaling pathway in thyroid cancer. Biosci Rep 2014;34(2):e00105. https://doi.org/10.1042/BSR20130134 PMid: 27919039
O'Neill HM, Holloway GP, Steinberg GR. AMPK regulation of fatty acid metabolism and mitochondrial biogenesis: implications for obesity. Mol Cell Endocrinol 2013;366(2):135-51. https://doi.org/10.1016/j.mce.2012.06.019 PMid: 22750049
Von Ballmoos C, Wiedenmann A, Dimroth P. Essentials for ATP synthesis by F1F0 ATP synthases. Annu Rev Biochem 2009;78:649-72. https://doi.org/10.1146/annurev.biochem.78.081307.104803 PMid: 19489730
Pan J, Sun LC, Tao YF, et al. ATP synthase ecto-?-subunit: a novel therapeutic target for breast cancer. J Transl Med 2011;9:211. https://doi.org/10.1186/1479-5876-9-211 PMid: 22152132
Calado A, Neves PM, Santos T, et al. The effect of flaxseed in breast cancer: a literature review. Frontiers in nutrition 2018;5:4. https://doi.org/10.3389/fnut.2018.00004 PMid: 29468163
Morshedzadeh N, Rahimlou M, Shahrokh S, et al. The effects of flaxseed supplementation on metabolic syndrome parameters, insulin resistance and inflammation in ulcerative colitis patients: An open-labeled randomized controlled trial. Phytother Res 2021;3587):3781-91. https://doi.org/10.1002/ptr.7081 PMid: 33856729
Luo J, Qi J, Wang W, et al. Antiobesity effect of flaxseed polysaccharide via inducing satiety due to leptin resistance removal and promoting lipid metabolism through the AMP-activated protein kinase (AMPK) signaling pathway. J Agric Food Chem 2019;67(25):7040-9. https://doi.org/10.1021/acs.jafc.9b02434 PMid: 31199141
Kang J, Park J, Park W, et al. A phytoestrogen secoisolariciresinol diglucoside induces browning of white adipose tissue and activates non-shivering thermogenesis through AMPK pathway. Pharmacol Res 2020;158:104852. https://doi.org/10.1016/j.phrs.2020.104852 PMid: 32438038
De Silva SF, Alcorn J. Flaxseed lignans as important dietary polyphenols for cancer prevention and treatment: Chemistry, pharmacokinetics, and molecular targets. Pharm. 2019;12(2):68. https://doi.org/10.3390/ph12020068 PMid: 31060335
Sharma M, Dadhwal K, Gat Y, et al. A review on newer techniques in the extraction of oleaginous flaxseed constituents. OCL 2019;26:14. https://doi.org/10.1051/ocl/2019006
Jamilian M, Tabassi Z, Reiner Ž, et al. The effects of n-3 fatty acids from flaxseed oil on genetic and metabolic profiles in patients with gestational diabetes mellitus: a randomized, double-blind, placebo-controlled trial. Br J Nutr 2020;123:792-9. https://doi.org/10.1017/S0007114519003416 PMid: 31902378
Wang H, Guo X, Wu Y, et al. Dynamic changes in phytochemical profiles identified key points of flaxseed capsule maturation for lignan accumulation. Ind Crops Prod 2020;147:112219. https://doi.org/10.1016/j.indcrop.2020.112219
Soltanian N, Janghorbani M. A randomized trial of the effects of flaxseed to manage constipation, weight, glycemia, and lipids in constipated patients with type 2 diabetes. Nutr Metab 2018;15:36. https://doi.org/10.1186/s12986-018-0273-z PMid: 29760761
Hasaniani N, Rahimlou M, Ahmadi AR, et al. The effect of flaxseed enriched yogurt on the glycemic status and cardiovascular risk factors in patients with type 2 diabetes mellitus: Randomized, open-labeled, controlled study. Clin Nutr Res 2019;8(4):284-95. https://doi.org/10.7762/cnr.2019.8.4.284 PMid: 31720254
Ravindran R, Swamy MK, Jaganathan R. Therapeutic potential of plant polyphenolics and their mechanistic action against various diseases. In: Swamy M, Akhtar M, editors. Natural Bio-Active Compounds. Springer, Singapore 2019:313-51. https://doi.org/10.1007/978-981-13-7205-6_14
Mohammed SG, Qoronfleh MW. Seeds. In: Essa M, Qoronfleh M, editors. Personalized Food Intervention and Therapy for Autism Spectrum Disorder Management. Advances in Neurobiology, vol 24. Springer, Cham 2020:421-67. https://doi.org/10.1007/978-3-030-30402-7_13 PMid: 32006367
Issaoui M, Delgado AM, Iommi C, et al. Dietary intakes of polyphenols in selected vegetables and fruits. In Polyphenols and the Mediterranean Diet. SpringerBriefs in Molecular Science. Springer, Cham 2020:33-54. https://doi.org/10.1007/978-3-030-41134-3_3
Bakhtiary M, Morvaridzadeh M, Agah S, et al. Effect of probiotic, prebiotic, and synbiotic supplementation on cardiometabolic and oxidative stress parameters in patients with chronic kidney disease: a systematic review and meta-analysis. Clin Ther 2021;43: e71-e96. https://doi.org/10.1016/j.clinthera.2020.12.021 PMid: 33526314
Bethel MA, Patel RA, Merrill P, et al. Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis. Lancet Diabetes Endocrinol 2018;6(2):105-13. https://doi.org/10.1016/S2213-8587(17)30412-6 PMid: 29221659
Nishi M. Diabetes mellitus and thyroid diseases. Diabetol Int 2018;9:108-12. https://doi.org/10.1007/s13340-018-0352-4 PMid: 30603357
Liang C, Bertoia ML, Ding Y, et al. Exenatide use and incidence of pancreatic and thyroid cancer: A retrospective cohort study. Diabetes Obes Metab 2019;21(4):1037-42. https://doi.org/10.1111/dom.13597 PMid: 30474347
Wynn A, Vacheron A, Zuber J, et al. Metformin is associated with increased survival in type 2 diabetes patients with pancreatic cancer and lymphoma. Am J Med Sci 2019;358(3):200-3. https://doi.org/10.1016/j.amjms.2019.06.002 PMid: 31324361
Feng M, Xiong G, Cao Z, et al. LAT2 regulates glutamine-dependent mTOR activation to promote glycolysis and chemoresistance in pancreatic cancer. J Exp Clin Cancer Res 2018;37:274. https://doi.org/10.1186/s13046-018-0947-4 PMid: 30419950
Winther L, Lohse J, Gabs S, et al. U.S. Patent No. 10036066. Washington, DC: U.S. Patent and Trademark Office; 2018.
Papathanassiu AE, MacDonald NJ, Bencsura A, et al. F1F0-ATP synthase functions as a co-chaperone of Hsp90-substrate protein complexes. Biochem Biophys Res Commun 2006;345(1):419-29. https://doi.org/10.1016/j.bbrc.2006.04.104 PMid: 16682002
Karamanlidis G, Nascimben L, Couper GS, et al. Defective DNA replication impairs mitochondrial biogenesis in human failing hearts. Circ Res 2010;106(9):1541-8. https://doi.org/10.1161/CIRCRESAHA.109.212753 PMid: 20339121
Shih SR, Chiu WY, Chang TC, et al. Diabetes and thyroid cancer risk: literature review. Exp Diabetes Res 2012;2012(1):578285. https://doi.org/10.1155/2012/578285 PMid: 22778714
Fox MM, Phoenix KN, Kopsiaftis SG, et al. AMP-activated protein kinase ?2 isoform suppression in primary breast cancer alters AMPK growth control and apoptotic signaling. Genes Cancer 2013;4(1-2):3-14. https://doi.org/10.1177/1947601913486346 PMid: 23946867
Okoshi R, Ozaki T, Yamamoto H, et al. Activation of AMP-activated protein kinase induces p53-dependent apoptotic cell death in response to energetic stress. J Biol Chem 2008;283(7):3979-87. https://doi.org/10.1074/jbc.M705232200 PMid: 18056705
Tannous S, Haykal T, Dhaini J, et al. The anti-cancer effect of flaxseed lignan derivatives on different acute myeloid leukemia cancer cells. Biomed Pharmacother 2020;132:110884. https://doi.org/10.1016/j.biopha.2020.110884 PMid: 33080470
Lin X, Gingrich JR, Bao W, et al. Effect of flaxseed supplementation on prostatic carcinoma in transgenic mice. Urology 2002;60(5):919-24. https://doi.org/10.1016/S0090-4295(02)01863-0 PMid: 12429338
Buckner AL, Buckner CA, Montaut S, et al. Treatment with flaxseed oil induces apoptosis in cultured malignant cells. Heliyon 2019;5(8):e02251. https://doi.org/10.1016/j.heliyon.2019.e02251 PMid: 31440598
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