Daucosterol linolenate from Sweet Potato Suppresses MCF7-Xenograft-Tumor Growth through Regulating PI3K/AKT Pathway

Abstract

Sweet potato is a functional food with potential antitumor properties, but the bioactive constituents and biological mechanisms remain unclear. In this study, we investigated the antitumor effect of daucosterol linolenate extracted from sweet potato and its potential mechanism. An MTT assay indicated that DLA inhibited the proliferation of breast cancer MCF-7 cells but had only weak effects on the proliferation of MDA-MB-231, 4T1, and MCF-10A cells. Flow cytometry analysis revealed that daucosterol linolenate induced apoptosis of MCF-7 cells. Experiments with MCF-7 xenograft in nude mice further confirmed that DLA inhibited tumor growth dose-dependently. After DLA treatment, the expressions of B-cell lymphoma 2 and vascular endothelial growth factor were decreased and that of cleaved caspase 3 was increased as compared to the TC group. DLA also down-regulated the expression of phosphoinositide 3-kinase/protein kinase B and repressed insulin-induced phosphoinositide 3-kinase/protein kinase B activation. Our findings suggest that DLA suppresses breast tumor growth through inactivating the phosphoinositide 3-kinase/protein kinase B pathway.

Key words

Ipomoea batatas - Convolvulaceae - Daucosterol linolenate - breast cancer - phosphoinositide 3-kinase/protein kinase B

• References

• 1 Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68: 394-424
• 2 Moulder S, Hortobagyi GN. Advances in the treatment of breast cancer. Clin Pharmacol Ter 2008; 83: 26-36
• 3 Perez EA. Treatment strategies for advanced hormone receptor-positive and human epidermal growth factor 2-negative breast cancer: the role of treatment order. Drug Resist Update 2016; 24: 13-22
• 4 Hassan M, Watari H, AbuAlmaaty A, Ohba Y, Sakuragi N. Apoptosis and molecular targeting therapy in cancer. Biomed Res Int 2014; 2014: 150845
• 5 Czabotar PE, Lessene G, Strasser A, Adams JM. Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol 2014; 15: 49-63
• 6 Huang M, Huang B, Li G, Zeng S. Apatinib affect VEGF-mediated cell proliferation, migration, invasion via blocking VEGFR2/RAF/MEK/ERK and PI3K/AKT pathways in cholangiocarcinoma cell. BMC Gastroenterol 2018; 18: 169
• 7 Food and Agriculture Organization of the United Nations. FAOSTAT. Available at: http://www.fao.org/faostat/en/%23data/QC Accessed December 16, 2019
• 8 Mohanraj R, Sivasankar S. Sweet potato (Ipomoea batatas [L.] Lam) – a valuable medicinal food: a review. J Med Food 2014; 17: 733-741
• 9 Kruger J, Breynaert A, Pieters L, Hermans N. Vegetable relishes, high in beta-carotene, increase the iron, zinc and beta-carotene nutritive values from cereal porridges. Int J Food Sci Nutr 2018; 69: 291-297
• 10 Wang L, Zhao Y, Zhou Q, Luo CL, Deng AP, Zhang ZC, Zhang JL. Characterization and hepatoprotective activity of anthocyanins from purple sweet potato (Ipomoea batatas L. cultivar Eshu No. 8). J Food Drug Anal 2017; 25: 607-618
• 11 Wang MM, Ma H, Tian C, Liu SS, Ye XL, Zhou DQ, Li YL, Hui N, Li XG. Bioassay-guided isolation of glycoprotein SPG-56 from sweet potato Zhongshu-1 and its anti-colon cancer activity in vitro and in vivo . J Funct Food 2017; 35: 315-324
• 12 Tang C, Sun J, Zhou B, Jin CH, Liu J, Kan J, Qian CL, Zhang NF. Effects of polysaccharides from purple sweet potatoes on immune response and gut microbiota composition in normal and cyclophosphamide treated mice. Food Funct 2018; 9: 937-950
• 13 Jeng TL, Lai CC, Liao TC, Lin SY, Sung JM. Effects of drying on caffeoylquinic acid derivative content and antioxidant capacity of sweet potato leaves. J Food Drug Anal 2015; 23: 701-708
• 14 Cordeiro N, Freitas N, Faria M, Gouveia M. Ipomoea batatas (L.) Lam.: a rich source of lipophilic phytochemicals. J Agric Food Chem 2013; 61: 12380-12384
• 15 Shi YP, Jia ZJ. Triterpenoids and other compounds from Euphorbia esula and E-petiolata. Indian J Chem Sect B 1997; 36: 1038-1043
• 16 Hardman WE. Dietary canola oil suppressed growth of implanted MDA-MB 231 human breast tumors in nude mice. Nutr Cancer 2007; 57: 177-183
• 17 Xu H, Li Y, Han B, Li Z, Wang B, Jiang P, Zhang J, Ma W, Zhou D, Li X, Ye X. Anti-breast-cancer activity exerted by beta-sitosterol-d-glucoside from sweet potato via upregulation of microRNA-10a and via the PI3K-Akt signaling pathway. J Agric Food Chem 2018; 66: 9704-9718
• 18 Esmaeili MA, Farimani MM. Inactivation of PI3K/Akt pathway and upregulation of PTEN gene are involved in daucosterol, isolated from Salvia sahendica, induced apoptosis in human breast adenocarcinoma cells. S Afr J Bot 2014; 93: 37-47
• 19 Mason-Ennis JK, LeMay-Nedjelski LP, Wiggins AKA, Thompson LU. Exploration of mechanisms of α-linolenic acid in reducing the growth of estrogen receptor positive breast cancer cells (MCF-7). J Funct Food 2016; 24: 513-519
• 20 Derks MGM, Blok EJ, Seynaeve C, Nortier JWR, Kranenbarg EMK, Liefers GJ, Putter H, Kroep JR, Rea D, Hasenburg A, Markopoulos C, Paridaens R, Smeets JBE, Dirix LY, van de Velde CJH. Adjuvant tamoxifen and exemestane in women with postmenopausal early breast cancer (TEAM): 10-year follow-up of a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2017; 18: 1211-1220
• 21 Ebeling FG, Stieber P, Untch M, Nagel D, Konecny GE, Schmitt UM, Seidel D. Serum CEA and CA 15-3 as prognostic factors in primary breast cancer. Br J Cancer 2002; 86: 1217
• 22 Fang C, Cao Y, Liu X, Zeng XT, Li Y. Serum CA125 is a predictive marker for breast cancer outcomes and correlates with molecular subtypes. Oncotarget 2017; 8: 63963-63970
• 23 Cheung KL, Graves CR, Robertson JF. Tumour marker measurements in the diagnosis and monitoring of breast cancer. Cancer Treat Rev 2000; 26: 91-102
• 24 Wang W, Xu X, Tian B, Wang Y, Du L, Sun T, Shi Y, Zhao X, Jing J. The diagnostic value of serum tumor markers CEA, CA19-9, CA125, CA15-3, and TPS in metastatic breast cancer. Clin Chim Acta 2017; 470: 51-55
• 25 Fontanella C, Ongaro E, Bolzonello S, Guardascione M, Fasola G, Aprile G. Clinical advances in the development of novel VEGFR2 inhibitors. Ann Transl Med 2014; 2: 123
• 26 Parveen A, Subedi L, Kim HW, Khan Z, Zahra Z, Farooqi MQ, Kim SY. Phytochemicals targeting VEGF and VEGF-related multifactors as anticancer therapy. J Clin Med 2019; 8: 350
• 27 Mayer IA, Arteaga CL. The PI3K/AKT pathway as a target for cancer treatment. Annu Rev Med 2016; 67: 11-28
• 28 Shrivastava S, Jeengar MK, Reddy VS, Reddy GB, Naidu VG. Anticancer effect of celastrol on human triple negative breast cancer: possible involvement of oxidative stress, mitochondrial dysfunction, apoptosis and PI3K/Akt pathways. Exp Mol Pathol 2015; 98: 313-327
• 29 Hu H, Juvekar A, Lyssiotis CA, Lien EC, Albeck JG, Oh D, Varma G, Hung YP, Ullas S, Lauring J, Seth P, Lundquist MR, Tolan DR, Grant AK, Needleman DJ, Asara JM, Cantley LC, Wulf GM. Phosphoinositide 3-kinase regulates glycolysis through mobilization of aldolase from the actin cytoskeleton. Cell 2016; 164: 433-446
• 30 Jiang P, Han B, Jiang L, Li Y, Yu Y, Xu H, Li Z, Zhou D, Jia X, Li X, Ye X. Simultaneous separation and quantitation of three phytosterols from the sweet potato, and determination of their anti-breast cancer activity. J Pharm Biomed Anal 2019; 174: 718-727
• 31 Fischer AH, Jacobson KA, Rose J, Zeller R. Hematoxylin and eosin staining of tissue and cell sections. CSH Protoc 2008; 2008: pdb.prot4986