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Cited by 169Cancer, Lipids, and MetabolismCoconut Research and ApplicationsCell death mechanisms and regulation

The lauric acid-activated signaling prompts apoptosis in cancer cells

Open access
Lappano, Rosamaria, Sebastiani, Anna, Cirillo, Francesca, Rigiracciolo, Damiano Cosimo, Galli, Giulia Raffaella, Curcio, Rosita, Malaguarnera, Roberta, Belfiore, Antonino +2 more·2017·Cell Death Discovery
DOI 10.1038/cddiscovery.2017.63PMC PMC5601385
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Abstract

Abstract The saturated medium-chain fatty-acid lauric acid (LA) has been associated to certain health-promoting benefits of coconut oil intake, including the improvement of the quality of life in breast cancer patients during chemotherapy. As it concerns the potential to hamper tumor growth, LA was shown to elicit inhibitory effects only in colon cancer cells. Here, we provide novel insights regarding the molecular mechanisms through which LA triggers antiproliferative and pro-apoptotic effects in both breast and endometrial cancer cells. In particular, our results demonstrate that LA increases reactive oxygen species levels, stimulates the phosphorylation of EGFR, ERK and c-Jun and induces the expression of c-fos. In addition, our data evidence that LA via the Rho-associated kinase-mediated pathway promotes stress fiber formation, which exerts a main role in the morphological changes associated with apoptotic cell death. Next, we found that the increase of p21 Cip1/WAF1 expression, which occurs upon LA exposure in a p53-independent manner, is involved in the apoptotic effects prompted by LA in both breast and endometrial cancer cells. Collectively, our findings may pave the way to better understand the anticancer action of LA, although additional studies are warranted to further corroborate its usefulness in more comprehensive therapeutic approaches.

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Research works printed but not linked: 55

  1. Layden BT, Angueira AR, Brodsky M, Durai V, Lowe WL Jr. Short chain fatty acids and their receptors: new metabolic targets. Transl Res 2013; 161: 131–140. 23146568
  2. Calder PC. Functional roles of fatty acids and their effects on human health. JPEN J Parenter Enteral Nutr 2015; 39: 18S–32S. 26177664
  3. Bocca C, Bozzo F, Gabriel L, Miglietta A. Conjugated linoleic acid inhibits Caco-2 cell growth via ERK-MAPK signaling pathway. J Nutr Biochem 2007; 18: 332–340. 16963252
  4. Engelbrecht AM, Toit-Kohn JL, Ellis B, Thomas M, Nell T, Smith R. Differential induction of apoptosis and inhibition of the PI3-kinase pathway by saturated, monounsaturated and polyunsaturated fatty acids in a colon cancer cell model. Apoptosis 2008; 13: 1368–1377. 18785011
  5. Jump DB, Clarke SD. Regulation of gene expression by dietary fat. Annu Rev Nutr 1999; 19: 63–90. 10448517
  6. Risérus U. Fatty acids and insulin sensitivity. Curr Opin Clin Nutr Metab Care 2008; 11: 100–105. 18301083
  7. Turcotte C, Chouinard F, Lefebvre JS, Flamand N. Regulation of inflammation by cannabinoids, the endocannabinoids 2-arachidonoyl-glycerol and arachidonoyl-ethanolamide, and their metabolites. J Leukoc Biol 2015; 97: 1049–1070. 25877930
  8. Dayrit FM. The properties of lauric acid and their significance in coconut oil. J Am Oil Chem Soc 2015; 92: 1–15.
  9. Kappally S, Shirwaikar A, Shirwaikar A. Coconut oil – a review of potential applications. Hygeia J D Med 2015; 7: 34–41.
  10. Eyres L, Eyres MF, Chisholm A, Brown RC. Coconut oil consumption and cardiovascular risk factors in humans. Nutr Rev 2016; 74: 267–280. 26946252 PMC4892314
  11. Silva RB, Silva-Júnior EV, Rodrigues LC, Andrade LH, da Silva SI, Harand W et al. A comparative study of nutritional composition and potential use of some underutilized tropical fruits of Arecaceae. An Acad Bras Cienc 2015; 87: 1701–1709. 26221983
  12. Silberstein T, Burg A, Blumenfeld J, Sheizaf B, Tzur T, Saphier O. Saturated fatty acid composition of human milk in Israel: a comparison between Jewish and Bedouin women. Isr Med Assoc J 2013; 15: 156–159. 23781748
  13. Huang WC, Tsai TH, Chuang LT, Li YY, Zouboulis CC, Tsai PJ. Anti-bacterial and anti-inflammatory properties of capric acid against Propionibacterium acnes: a comparative study with lauric acid. J Dermatol Sci 2014; 73: 232–240. 24284257
  14. Temme EH, Mensink RP, Hornstra G. Comparison of the effects of diets enriched in lauric, palmitic, or oleic acids on serum lipids and lipoproteins in healthy women and men. Am J Clin Nutr 1996; 63: 897–903. 8644684
  15. Alves NF, de Queiroz TM, de Almeida Travassos R, Magnani M, de Andrade Braga V. Acute treatment with lauric acid reduces blood pressure and oxidative stress in spontaneously hypertensive rats. Basic Clin Pharmacol Toxicol 2017; 120: 348–353. 28054477
  16. Veeresh Babu SV, Veeresh B, Patil AA, Warke YB. Lauric acid and myristic acid prevent testosterone induced prostatic hyperplasia in rats. Eur J Pharmacol 2010; 626: 262–265. 19786012
  17. Fauser JK, Matthews GM, Cummins AG, Howarth GS. Induction of apoptosis by the medium-chain length fatty acid lauric acid in colon cancer cells due to induction of oxidative stress. Chemotherapy 2013; 59: 214–224. 24356281
  18. Weng WH, Leung WH, Pang YJ, Hsu HH. Lauric acid can improve the sensitization of Cetuximab in KRAS/BRAF mutated colorectal cancer cells by retrievable microRNA-378 expression. Oncol Rep 2016; 35: 107–116. 26496897
  19. Law KS, Azman N, Omar EA, Musa MY, Yusoff NM, Sulaiman SA et al. The effects of virgin coconut oil (VCO) as supplementation on quality of life (QOL) among breast cancer patients. Lipids Health Dis 2014; 13: 139. 25163649 PMC4176590
  20. Narayanan A, Baskaran SA, Amalaradjou MA, Venkitanarayanan K. Anticarcinogenic properties of medium chain fatty acids on human colorectal, skin and breast cancer cells in vitro. Int J Mol Sci 2015; 16: 5014–5027. 25749477 PMC4394462
  21. Abdullah FO, Hussain FH, Mannucci B, Lappano R, Tosi S, Maggiolini M et al. Composition, antifungal and antiproliferative activities of the hydrodistilled oils from leaves and flower heads of pterocephalus nestorianus Nab. Chem Biodivers 2017; 14: e1700009. 28217981
  22. Jaffe AB, Hall A. Rho GTPases: biochemistry and biology. Annu Rev Cell Dev Biol 2005; 21: 247–269. 16212495
  23. Ibarguren M, López DJ, Escribá PV. The effect of natural and synthetic fatty acids on membrane structure, microdomain organization, cellular functions and human health. Biochim Biophys Acta 2014; 1838: 1518–1528. 24388951
  24. Wanders RJ, Ruiter JP, IJLst L, Waterham HR, Houten SM. The enzymology of mitochondrial fatty acid beta-oxidation and its application to follow-up analysis of positive neonatal screening results. J Inherit Metab Dis 2010; 33: 479–494. 20490924 PMC2946543
  25. Estadella D, da Penha Oller do Nascimento CM, Oyama LM, Ribeiro EB, Dâmaso AR, de Piano A. Lipotoxicity: effects of dietary saturated and transfatty acids. Mediators Inflamm 2013; 2013: 137579. 23509418 PMC3572653
  26. Babu AS, Veluswamy SK, Arena R, Guazzi M, Lavie CJ. Virgin coconut oil and its potential cardioprotective effects. Postgrad Med 2014; 126: 76–83. 25387216
  27. Mumme K, Stonehouse W. Effects of medium-chain triglycerides on weight loss and body composition: a meta-analysis of randomized controlled trials. J Acad Nutr Diet 2015; 115: 249–263. 25636220
  28. McCarty MF, DiNicolantonio JJ. Lauric acid-rich medium-chain triglycerides can substitute for other oils in cooking applications and may have limited pathogenicity. Open Heart 2016; 3: e000467. 27547436 PMC4975867
  29. Stanhope JM, Sampson VM, Prior IA. The Tokelau Island Migrant Study: serum lipid concentration in two environments. J Chronic Dis 1981; 34: 45–55. 7462380
  30. Reddy BS, Maeura Y. Tumor promotion of dietary fat in azoxymethane-induced colon carcinogenesis in female F 344 rats. J Natl Cancer Inst 1984; 72: 745–750. 6583457
  31. Cohen LA, Thompson DO, Maeura Y, Choi K, Blank ME, Rose DP. Dietary fat and mammary cancer. Promoting effects of different dietary fats on N-nitrosomethylurea- induced rat mammary tumorigenesis. J Natl Cancer Inst 1986; 77: 33–42. 3459924
  32. Fukui M, Kang KS, Okada K, Zhu BT. EPA, an omega-3 fatty acid, induces apoptosis in human pancreatic cancer cells: role of ROS accumulation, caspase-8 activation, and autophagy induction. J Cell Biochem 2013; 114: 192–203. 22903547
  33. Shin S, Jing K, Jeong S, Kim N, Song KS, Heo JY et al. The omega-3 polyunsaturated fatty acid DHA induces simultaneous apoptosis and autophagy via mitochondrial ROS-mediated Akt-mTOR signaling in prostate cancer cells expressing mutant p53. Biomed Res Int 2013; 2013: 568671. 23841076 PMC3691929
  34. Song Y, Li X, Li Y, Li N, Shi X, Ding H et al. Non-esterified fatty acids activate the ROS-p38-p53/Nrf2 signaling pathway to induce bovine hepatocyte apoptosis in vitro. Apoptosis 2014; 19: 984–997. 24699798
  35. Lehto VP. EGF receptor: which way to go? FEBS Lett 2001; 491: 1–3. 11226407
  36. Pellegrin S, Mellor H. Actin stress fibres. J Cell Sci 2007; 120: 3491–3499. 17928305
  37. Sebbagh M, Renvoizé C, Hamelin J, Riché N, Bertoglio J, Bréard J. Caspase-3-mediated cleavage of ROCK I induces MLC phosphorylation and apoptotic membrane blebbing. Nat Cell Biol 2001; 3: 346–352. 11283607
  38. Huang CY, Liang CM, Chu CL, Peng JM, Liang SM. A fibrillar form of fibronectin induces apoptosis by activating SHP-2 and stress fiber formation. Apoptosis 2010; 15: 915–926. 20414729
  39. Xiao L, Eto M, Kazanietz MG. ROCK mediates phorbol ester-induced apoptosis in prostate cancer cells via p21Cip1 up-regulation and JNK. J Biol Chem 2009; 284: 29365–29375. 19667069 PMC2785568
  40. Coleman ML, Sahai EA, Yeo M, Bosch M, Dewar A, Olson MF. Membrane blebbing during apoptosis results from caspase-mediated activation of ROCK I. Nat Cell Biol 2001; 3: 339–345. 11283606
  41. Etienne-Manneville S, Hall A. Rho GTPases in cell biology. Nature 2002; 420: 629–635. 12478284
  42. Del Re DP, Miyamoto S, Brown JH. RhoA/Rho kinase up-regulate Bax to activate a mitochondrial death pathway and induce cardiomyocyte apoptosis. J Biol Chem 2007; 282: 8069–8078. 17234627
  43. Lai JM, Hsieh CL, Chang ZF. Caspase activation during phorbol ester-induced apoptosis requires ROCK-dependent myosin-mediated contraction. J Cell Sci 2003; 116: 3491–3501. 12865435
  44. Gartel AL. p21(WAF1/CIP1) and cancer: a shifting paradigm? Biofactors 2009; 35: 161–164. 19449443
  45. Gartel AL, Tyner AL. The role of the cyclin-dependent kinase inhibitor p21 in apoptosis. Mol Cancer Ther 2002; 1: 639–649. 12479224
  46. Karimian A, Ahmadi Y, Yousefi B. Multiple functions of p21 in cell cycle, apoptosis and transcriptional regulation after DNA damage. DNA Repair (Amst) 2016; 42: 63–71. 27156098
  47. Dotto GP. p21(WAF1/Cip1): more than a break to the cell cycle? Biochim Biophys Acta 2000; 1471: M43–M56. 10967424
  48. Ocker M, Schneider-Stock R. Histone deacetylase inhibitors: signalling towards p21cip1/waf1. Int J Biochem Cell Biol 2007; 39: 1367–1374. 17412634
  49. Gogada R, Amadori M, Zhang H, Jones A, Verone A, Pitarresi J et al. Curcumin induces Apaf-1-dependent, p21-mediated caspase activation and apoptosis. Cell Cycle 2011; 10: 4128–4137. 22101335 PMC3272293
  50. Zhao B, He T. Chidamide, a histone deacetylase inhibitor, functions as a tumor inhibitor by modulating the ratio of Bax/Bcl-2 and P21 in pancreatic cancer. Oncol Rep 2015; 33: 304–310. 25384499
  51. Kondo S, Barna BP, Kondo Y, Tanaka Y, Casey G, Liu J et al. WAF1/CIP1 increases the susceptibility of p53 non-functional malignant glioma cells to cisplatin-induced apoptosis. Oncogene 1996; 13: 1279–1285. 8808702
  52. Lincet H, Poulain L, Remy JS, Deslandes E, Duigou F, Gauduchon P et al. The p21(cip1/waf1) cyclin-dependent kinase inhibitor enhances the cytotoxic effect of cisplatin in human ovarian carcinoma cells. Cancer Lett 2000; 161: 17–26. 11078909
  53. Gerdes MJ, Myakishev M, Frost NA, Rishi V, Moitra J, Acharya A et al. Activator protein-1 activity regulates epithelial tumor cell identity. Cancer Res 2006; 66: 7578–7588. 16885357
  54. Lappano R, Santolla MF, Pupo M, Sinicropi MS, Caruso A, Rosano C et al. MIBE acts as antagonist ligand of both estrogen receptor α and GPER in breast cancer cells. Breast Cancer Res 2012; 14: R12. 22251451 PMC3496129
  55. Santolla MF, Avino S, Pellegrino M, De Francesco EM, De Marco P, Lappano R et al. SIRT1 is involved in oncogenic signaling mediated by GPER in breast cancer. Cell Death Dis 2015; 6: e1834. 26225773 PMC4650744

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Authors
Lappano, R., Sebastiani, A., Cirillo, F., Rigiracciolo, D. C., Galli, G. R., Curcio, R., Malaguarnera, R., Belfiore, A., Cappello, A. R., & Maggiolini, M.
Affiliations
  • University of Calabria (IT)
  • Magna Graecia University (IT)
Corresponding author
  • Lappano, Rosamaria
  • Cappello, Anna Rita
ORCID
Venue
Cell Death Discovery
Publisher
Springer Science and Business Media LLC
Published
2017-09-18
Volume
3
Issue
1
Pages
17063-17063
ISSN
2058-7716 (ISSN-L)
DOI
10.1038/cddiscovery.2017.63
PMC
PMC5601385
OpenAlex
W2754703152
Cited by
169
References
2
Citations by year
2026: 16 · 2025: 25 · 2024: 25 · 2023: 19 · 2022: 20 · 2021: 20 · 2020: 28 · 2019: 9 · 2018: 5 · 2017: 2
FWCI
4.04
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Death Discovery (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Archive of Doctoral Theses and Digital Collections (University of Calabria) (submittedVersion)
Funders
Associazione Italiana per la Ricerca sul Cancro (IG 19242, IG16719)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
  • Physical Sciences › Chemistry › Inorganic Chemistry › Coconut Research and Applications
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Keywords
lauric acid, medium-chain fatty acids, coconut oil, apoptosis, breast cancer, endometrial cancer, reactive oxygen species, EGFR phosphorylation, ERK signaling, c-Jun phosphorylation, c-fos, Rho kinase, stress fiber formation, p21 CIP1/WAF1, p53-independent apoptosis

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