Effects of Somatostatin and Vitamin C on the Fatty Acid Profile of Breast Cancer Cell Membranes

Author(s): Aysegul Hanikoglu, Ertan Kucuksayan, Ferhat Hanikoglu, Tomris Ozben*, Georgia Menounou, Anna Sansone, Chrys Chatgilialoglu, Giuseppe Di Bella, Carla Ferreri.

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 19 , Issue 15 , 2019

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Graphical Abstract:


Abstract:

Background: Vitamin C (Vit C) is an important physiological antioxidant with growing applications in cancer. Somatostatin (SST) is a natural peptide with growth inhibitory effect in several mammary cancer models.

Objective: The combined effects of SST and Vit C supplementation have never been studied in breast cancer cells so far.

Methods: We used MCF-7 and MDA-MB231 breast cancer cells incubated with SST for 24h, in the absence and presence of Vit C, at their EC50 concentrations, to evaluate membrane fatty acid-profiles together with the follow-up of EGFR and MAPK signaling pathways.

Results: The two cell lines gave different membrane reorganization: in MCF-7 cells, decrease of omega-6 linoleic acid and increase of omega-3 fatty acids (Fas) occurred after SST and SST+Vit C incubations, the latter also showing significant increases in MUFA, docosapentaenoic acid and mono-trans arachidonic acid levels. In MDA-MB231 cells, SST+Vit C incubation induced significant membrane remodeling with an increase of stearic acid and mono-trans-linoleic acid isomer, diminution of omega-6 linoleic, arachidonic acid and omega-3 (docosapentaenoic and docosadienoic acids). Distinct signaling pathways in these cell lines were studied: in MCF-7 cells, incubations with SST and Vit C, alone or in combination significantly decreased EGFR and MAPK signaling, whereas in MDA-MB231 cells, SST and Vit C incubations, alone or combined, decreased p- P44/42 MAPK levels, and increased EGFR levels.

Conclusion: Our results showed that SST and Vit C can be combined to induce membrane fatty acid changes, including lipid isomerization through a specific free radical-driven process, influencing signaling pathways.

Keywords: Somatostatin, Vitamin C, membrane fatty acid profile, breast cancer, cell signaling, gas chromatography.

[1]
Rayne, S.; Schnippel, K.; Kruger, D.; Benn, C.A.; Firnhaber, C. Delay to diagnosis and breast cancer stage in an urban South African breast clinic. S. Afr. Med. J., 2019, 109(3), 159-163.
[2]
Blackburn, G.L.; Copeland, T.; Khaodhiar, L.; Buckley, R.B. Diet and breast cancer. J. Womens Health (Larchmt.), 2003, 12(2), 183-192.
[3]
Esquivel-Velázquez, M.; Ostoa-Saloma, P.; Palacios-Arreola, M.I.; Nava-Castro, K.E.; Castro, J.I.; Morales-Montor, J. The role of cytokines in breast cancer development and progression. J. Interferon Cytokine Res., 2015, 35(1), 1-16.
[4]
Vahid, F.; Shivappa, N.; Karamati, M.; Naeini, A.J.; Hebert, J.R.; Davoodi, S.H. Association between Dietary Inflammatory Index (DII) and risk of prediabetes: A case-control study. Appl. Physiol. Nutr. Metab., 2017, 42(4), 399-404.
[5]
Dey, G.; Bharti, R.; Sen, R.; Mandal, M. Microbial amphiphiles: a class of promising new-generation anticancer agents. Drug Discov. Today, 2015, 20(1), 136-146.
[6]
Hilliard, T.S.; Miklossy, G.; Chock, C.; Yue, P.; Williams, P.; Turkson, J. 15α-methoxypuupehenol induces antitumor effects in vitro and in vivo against human glioblastoma and breast cancer models. Mol. Cancer Ther., 2017, 16(4), 601-613.
[7]
Fakai, M.I.; Abd Malek, S.N.; Karsani, S.A. Induction of apoptosis by chalepin through phosphatidylserine externalisations and DNA fragmentation in breast cancer cells (MCF7). Life Sci., 2019, 220, 186-193.
[8]
Yu, Y.L.; Chou, R.H.; Liang, J.H.; Chang, W.J.; Su, K.J.; Tseng, Y.J.; Huang, W.C.; Wang, S.C.; Hung, M.C. Targeting the EGFR/PCNA signaling suppresses tumor growth of triple-negative breast cancer cells with cell-penetrating PCNA peptides. PLoS One, 2013, 8(4)e61362
[9]
Lumachi, F.; Chiara, G.B.; Foltran, L.; Basso, S.M. Proteomics as a guide for personalized adjuvant chemotherapy in patients with early breast cancer. Cancer Genomics Proteomics, 2015, 12(6), 385-390.
[10]
Williams, C.B.; Soloff, A.C.; Ethier, S.P.; Yeh, E.S. Perspectives on epidermal growth factor receptor regulation in triple-negative breast cancer: Ligand-mediated mechanisms of receptor regulation and potential for clinical targeting. Adv. Cancer Res., 2015, 127, 253-281.
[11]
Mense, S.M.; Singh, B.; Remotti, F.; Liu, X.; Bhat, H.K. Vitamin C and alpha-naphthoflavone prevent estrogen-induced mammary tumors and decrease oxidative stress in female ACI rats. Carcinogenesis, 2009, 30(7), 1202-1208.
[12]
Nagappan, A.; Park, K.I.; Park, H.S.; Kim, J.A.; Hong, G.E.; Kang, S.R.; Lee, D.H.; Kim, E.H.; Lee, W.S.; Won, C.K.; Kim, G.S. Vitamin C induces apoptosis in AGS cells by down-regulation of 14-3-3σ via a mitochondrial dependent pathway. Food Chem., 2012, 135(3), 1920-1928.
[13]
Buettner, G.R. The pecking order of free radicals and antioxidants: lipid peroxidation, alpha-tocopherol, and ascorbate. Arch. Biochem. Biophys., 1993, 300(2), 535-543.
[14]
Mason, S.A.; Della Gatta, P.A.; Snow, R.J.; Russell, A.P.; Wadley, G.D. Ascorbic acid supplementation improves skeletal muscle oxidative stress and insulin sensitivity in people with type 2 diabetes: Findings of a randomized controlled study. Free Radic. Biol. Med., 2016, 93, 227-238.
[15]
Grzesik, M.; Bartosz, G.; Stefaniuk, I.; Pichla, M.; Namieśnik, J.; Sadowska-Bartosz, I. Dietary antioxidants as a source of hydrogen peroxide. Food Chem., 2019, 278, 692-699.
[16]
Rawal, M.; Schroeder, S.R.; Wagner, B.A.; Cushing, C.M.; Welsh, J.L.; Button, A.M.; Du, J.; Sibenaller, Z.A.; Buettner, G.R.; Cullen, J.J. Manganoporphyrins increase ascorbate-induced cytotoxicity by enhancing H2O2 generation. Cancer Res., 2013, 73(16), 5232-5241.
[17]
Jacobs, C.; Hutton, B.; Ng, T.; Shorr, R.; Clemons, M. Is there a role for oral or intravenous ascorbate (vitamin C) in treating patients with cancer? A systematic review. Oncologist, 2015, 20(2), 210-223.
[18]
Guerriero, E.; Sorice, A.; Capone, F.; Napolitano, V.; Colonna, G.; Storti, G.; Castello, G.; Costantini, S. Vitamin C effect on mitoxantrone-induced cytotoxicity in human breast cancer cell lines. PLoS One, 2014, 9(12)e115287
[19]
Yiang, G.T.; Chou, P.L.; Hung, Y.T.; Chen, J.N.; Chang, W.J.; Yu, Y.L.; Wei, C.W. Vitamin C enhances anticancer activity in methotrexate-treated Hep3B hepatocellular carcinoma cells. Oncol. Rep., 2014, 32(3), 1057-1063.
[20]
Camarena, V.; Wang, G. The epigenetic role of vitamin C in health and disease. Cell. Mol. Life Sci., 2016, 73(8), 1645-1658.
[21]
Sen, S.; Kawahara, B.; Chaudhuri, G. Maintenance of higher H2O2 levels, and its mechanism of action to induce growth in breast cancer cells: Important roles of bioactive catalase and PP2A. Free Radic. Biol. Med., 2012, 53(8), 1541-1551.
[22]
Chua, P.J.; Yip, G.W.; Bay, B.H. Cell cycle arrest induced by hydrogen peroxide is associated with modulation of oxidative stress related genes in breast cancer cells. Exp. Biol. Med. (Maywood), 2009, 234(9), 1086-1094.
[23]
Mata, A.M.; Carvalho, R.M.; Alencar, M.V.; Cavalcante, A.A.; Silva, B.B. Ascorbic acid in the prevention and treatment of cancer. Rev Assoc Med Bras (1992), 2016, 62(7), 680-686.
[24]
Chen, Q.; Espey, M.G.; Krishna, M.C.; Mitchell, J.B.; Corpe, C.P.; Buettner, G.R.; Shacter, E.; Levine, M. Pharmacologic ascorbic acid concentrations selectively kill cancer cells: Action as a pro-drug to deliver hydrogen peroxide to tissues. Proc. Natl. Acad. Sci. USA, 2005, 102(38), 13604-13609.
[25]
Lee, S.J.; Jeong, J.H.; Lee, I.H.; Lee, J.; Jung, J.H.; Park, H.Y.; Lee, D.H.; Chae, Y.S. Effect of high-dose vitamin C combined with anti-cancer treatment on breast cancer cells. Anticancer Res., 2019, 39(2), 751-758.
[26]
Park, S. The effects of high concentrations of vitamin C on cancer cells. Nutrients, 2013, 5(9), 3496-3505.
[27]
Harris, A.G. Somatostatin and somatostatin analogues: pharmacokinetics and pharmacodynamic effects. Gut, 1994, 35(3), S1-S4.
[28]
O’Toole, T.J.; Sharma, S. Physiology; Somatostatin, 2019.
[29]
Kristinsson, H.; Sargsyan, E.; Manell, H.; Smith, D.M.; Göpel, S.O.; Bergsten, P. Basal hypersecretion of glucagon and insulin from palmitate-exposed human islets depends on FFAR1 but not decreased somatostatin secretion. Sci. Rep., 2017, 7(1), 4657.
[30]
Reubi, J.C.; Torhorst, J. The relationship between somatostatin, epidermal growth factor, and steroid hormone receptors in breast cancer. Cancer, 1989, 64(6), 1254-1260.
[31]
Watt, H.L.; Kumar, U. Colocalization of somatostatin receptors and epidermal growth factor receptors in breast cancer cells. Cancer Cell Int., 2006, 6, 5.
[32]
Keskin, O.; Yalcin, S. A review of the use of somatostatin analogs in oncology. OncoTargets Ther., 2013, 6, 471-483.
[33]
Watt, H.L.; Kharmate, G.; Kumar, U. Biology of somatostatin in breast cancer. Mol. Cell. Endocrinol., 2008, 286(1-2), 251-261.
[34]
He, Y.; Yuan, X.M.; Lei, P.; Wu, S.; Xing, W.; Lan, X.L.; Zhu, H.F.; Huang, T.; Wang, G.B.; An, R.; Zhang, Y.X.; Shen, G.X. The antiproliferative effects of somatostatin receptor subtype 2 in breast cancer cells. Acta Pharmacol. Sin., 2009, 30(7), 1053-1059.
[35]
Cort, A.; Ozben, T.; Melchiorre, M.; Chatgilialoglu, C.; Ferreri, C.; Sansone, A. Effects of bleomycin and antioxidants on the fatty acid profile of testicular cancer cell membranes. Biochim. Biophys. Acta, 2016, 1858(2), 434-441.
[36]
Chatgilialoglu, C.; Ferreri, C.; Melchiorre, M.; Sansone, A.; Torreggiani, A. Lipid geometrical isomerism: From chemistry to biology and diagnostics. Chem. Rev., 2014, 114(1), 255-284.
[37]
Ediriweera, M.K.; Tennekoon, K.H.; Samarakoon, S.R.; Thabrew, I.; de Silva, E.D. Protective effects of six selected dietary compounds against leptin-induced proliferation of oestrogen receptor positive (MCF-7) breast cancer cells. Medicines (Basel), 2017, 4(3)E56
[38]
Bradford, M.M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem., 1976, 72, 248-254.
[39]
Kamphorst, J.J.; Cross, J.R.; Fan, J.; de Stanchina, E.; Mathew, R.; White, E.P.; Thompson, C.B.; Rabinowitz, J.D. Hypoxic and Ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids. Proc. Natl. Acad. Sci. USA, 2013, 110(22), 8882-8887.
[40]
Igal, R.A. Roles of StearoylCoA desaturase-1 in the Regulation of cancer cell growth, survival and tumorigenesis. Cancers (Basel), 2011, 3(2), 2462-2477.
[41]
Bolognesi, A.; Chatgilialoglu, A.; Polito, L.; Ferreri, C. Membrane lipidome reorganization correlates with the fate of neuroblastoma cells supplemented with fatty acids. PLoS One, 2013, 8(2)e55537
[42]
Azrad, M.; Turgeon, C.; Demark-Wahnefried, W. Current evidence linking polyunsaturated Fatty acids with cancer risk and progression. Front. Oncol., 2013, 3, 224.
[43]
Hardy, S.; El-Assaad, W.; Przybytkowski, E.; Joly, E.; Prentki, M.; Langelier, Y. Saturated fatty acid-induced apoptosis in MDA-MB-231 breast cancer cells. A role for cardiolipin. J. Biol. Chem., 2003, 278(34), 31861-31870.
[44]
Rysman, E.; Brusselmans, K.; Scheys, K.; Timmermans, L.; Derua, R.; Munck, S.; Van Veldhoven, P.P.; Waltregny, D.; Daniëls, V.W.; Machiels, J.; Vanderhoydonc, F.; Smans, K.; Waelkens, E.; Verhoeven, G.; Swinnen, J.V. De novo lipogenesis protects cancer cells from free radicals and chemotherapeutics by promoting membrane lipid saturation. Cancer Res., 2010, 70(20), 8117-8126.
[45]
Lykakis, I.N.; Ferreri, C.; Chatgilialoglu, C. The sulfhydryl radical (HS(.)/S(.-)): a contender for the isomerization of double bonds in membrane lipids. Angew. Chem. Int. Ed. Engl., 2007, 46(11), 1914-1916.
[46]
Uetaki, M.; Tabata, S.; Nakasuka, F.; Soga, T.; Tomita, M. Metabolomic alterations in human cancer cells by vitamin C-induced oxidative stress. Sci. Rep., 2015, 5, 13896.
[47]
War, S.A.; Kim, B.; Kumar, U. Human somatostatin receptor-3 distinctively induces apoptosis in MCF-7 and cell cycle arrest in MDA-MB-231 breast cancer cells. Mol. Cell. Endocrinol., 2015, 413, 129-144.
[48]
Gu, X.; Han, D.; Chen, W.; Zhang, L.; Lin, Q.; Gao, J.; Fanning, S.; Han, B. SIRT1-mediated FoxOs pathways protect against apoptosis by promoting autophagy in osteoblast-like MC3T3-E1 cells exposed to sodium fluoride. Oncotarget, 2016, 7(40), 65218-65230.


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Article Details

VOLUME: 19
ISSUE: 15
Year: 2019
Page: [1899 - 1909]
Pages: 11
DOI: 10.2174/1871520619666190930130732
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