Hypochlorite-induced oxidative stress elevates the capability of HDL in promoting breast cancer metastasis

Journal of Translational Medicine

Lemin Zheng³  Belinda Willard⁴  Youyi Zhang⁵  Wen-bing Sun⁶  Fangzhu Yu⁵  Jinge Kong⁵  Chenguang Niu⁵  Yijing Ma⁵  Yubin He²  Baoqi Yu⁵  Yangyu Zhao¹  Xiaofeng Lv²  Hui Ren⁵  Bing Pan⁵ 

[1] The Department of Obstetrics and Gynecology and the Institute of Vascular Medicine, Peking University Third Hospital, Beijing 100191, China;The Department of Cardiovascular Medicine and the Department of endocrinology, the Military General Hospital of Beijing, Beijing 100700, China;Institute of Cardiovascular Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing 100191, China;Proteomics Laboratory, Cleveland Clinic, Cleveland, OH 44195, USA;The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, School of Basic Medical Sciences, and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Peking University Health Science Center, Beijing 100191, China;Department of Hepatobiliary Surgery, West Campus, Beijing Chao-yang Hospital, Capital Medical University, Beijing 100043, China

关键词: High-density lipoprotein;    Metastasis;    Oxidative stress;    Breast cancer;   

Others  :  1206016
DOI  :  10.1186/1479-5876-10-65

 received in 2011-12-19, accepted in 2012-03-30,  发布年份 2012

【 摘 要 】

Background

Previous studies suggest that oxidative stress plays an important role in the development of breast cancer. There is a significant inverse relationship between HDL and the risk and mortality of breast cancer. However, it is well known that under conditions of oxidative stress, such as breast cancer, HDL can be oxidatively modifiedand these modifications may have an effect on the functions of HDL. The purpose of this study is to determine the different effects of normal and oxidized (caused by hypochlorite-induced oxidative stress) HDL on breast cancer cell metastasis.

Methods

Human breast cancer cell lines were treated with normal and hypochlorite-oxidized HDL, and then cell metastasis potency in vivo and the abilities of migration, invasion, adhesion to HUVEC and ECM in vitro were examined. Integrin expression and PKC activity were evaluated, and PKC inhibitor and PKC siRNA was applied.

Results

We found hypochlorite-oxidized HDL dramatically promotes breast cancer cell pulmonary metastasis (133.4% increase at P < 0.0 l for MDA-MB-231 by mammary fat pad injection; 164.3% increase at P < 0.01 for MCF7 by tail vein injection) and hepatic metastasis (420% increase at P < 0.0 l for MDA-MB-231 by mammary fat pad injection; 1840% fold increase at P < 0.001 for MCF7 by tail vein injection) in nude mice, and stimulates higher cell invasion (85.1% increase at P < 0.00 l for MDA-MB-231; 88.8% increase at P < 0.00 l for MCF7;), TC-HUVEC adhesion (43.4% increase at P < 0.00 l for MDA-MB-231; 35.2% increase at P < 0.00 l for MCF7), and TC-ECM attachment (41.0% increase at P < 0.00 l for MDA-MB-231; 26.7% increase at P < 0.05 for MCF7) in vitro compared with normal HDL. The data also shows that the PKC pathway is involved in the abnormal actions of hypochlorite-oxidized HDL.

Conclusions

Our study demonstrated that HDL under hypochlorite-induced oxidative stress stimulates breast cancer cell migration, invasion, adhesion to HUVEC and ECM, thereby promoting metastasis of breast cancer. These results suggest that HDL-based treatments should be considered for treatment of breast cancer patients.

【 授权许可】

   
2012 Pan et al; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Parkin DM, Bray F, Ferlay J, Pisani P: Global Cancer Statistics, 2002. CA Cancer J Clin 2005, 55:74-108.
• [2]World Health Organization: The World Health Report. Geneva: WHO; 1997.
• [3]Domínguez MG, Jiang X, Castelao JE: Lipid peroxidation, oxidative stress genes and dietary factors in breast cancer protection: a hypothesis. Breast Cancer Res 2007, 9:201-211.
• [4]Sand C, Peters SLM, Mathy M-J: The effects of hypochlorite-induced oxidative stress on presynaptic M2-receptors at sympathetic nerve endings in the rat tail artery. Auton Autacoid Pharmacol 2002, 22:127-132.
• [5]Wittekind C, Neid M: Cancer invasion and metastasis. Oncology 2005, 69(S1):14-16.
• [6]Gupta GP, Massagué J: Cancer metastasis: building a framework. Cell 2006, 127:679-695.
• [7]Woodhouse EC, Chuaqui RF, Liotta LA: General mechanisms of metastasis. Cancer 1997, 80:1529-1537.
• [8]Rathinam R, Alahari SK: Important role of integrins in the cancer biology. Cancer Metastasis Rev 2010, 29:223-237.
• [9]Cohen MB, Griebling TL, Ahaghotu CA, Rokhlin OW, Ross JS: Cellular adhesion molecules in urologic malignancies. Am J Clin Pathol 1997, 107:56-63.
• [10]Tan M, Li P, Sun M, Yin G, Yu D: Upregulation and activation of PKC alpha by ErbB2 through Src promotes breast cancer cell invasion that can be blocked by combined treatment with PKC alpha and Src inhibitors. Oncogene 2006, 25:3286-3295.
• [11]Mackay HJ, Twelves CJ: Protein kinase C: a target for anticancer drugs. Endocr Relat Cancer 2003, 10:389-396.
• [12]Ng T, Shima D, Squire A, Bastiaens PI, Gschmeissner S, Humphries MJ, Parker PJ: PKC alpha regulates beta1 integrin-dependent cell motility through association and control of integrin traffic. EMBO J 1999, 18:3909-3923.
• [13]Parsons M, Keppler MD, Kline A, Messent A, Humphries MJ, Gilchrist R, Hart IR, Quittau-Prevostel C, Hughes WE, Parker PJ, Ng T: Site-directed perturbation of protein kinase C- integrin interaction blocks carcinoma cell chemotaxis. Mol Cell Biol 2002, 22:5897-5911.
• [14]Kolanus W, Seed B: Integrins and inside-out signal transduction: converging signals from PKC and PIP3. Curr Opin Cell Biol 1997, 9:725-731.
• [15]Assmann G, Nofer JR: Atheroprotective effects of high-density lipoproteins. Annu Rev Med 2003, 54:321-341.
• [16]Kontush A, Chapman MJ: Functionally defective high-density lipoprotein: a new therapeutic target at the crossroads of dyslipidemia, inflammation, and atherosclerosis. Pharmacol Rev 2006, 58:342-374.
• [17]Jafri H, Alsheikh-Ali AA, Karas RH: Baseline and on-treatment high-density lipoprotein cholesterol and the risk of cancer in randomized controlled trials of lipid-altering therapy. J Am Coll Cardiol 2010, 55:2846-2854.
• [18]Moorman PG, Hulka BS, Hiatt RA, Krieger N, Newman B, Vogelman JH, Orentreich N: Association between high-density lipoprotein cholesterol and breast cancer varies by menopausal status. Cancer Epidemiol Biomarkers Prev 1998, 7:483-488.
• [19]Kucharska-Newton AM, Rosamond WD, Mink PJ, Alberg AJ, Shahar E, Folsom AR: HDL-cholesterol and incidence of breast cancer in the ARIC cohort study. Ann Epidemiol 2008, 18:671-677.
• [20]Furberg AS, Veierød MB, Wilsgaard T, Bernstein L, Thune I: Serum high-density lipoprotein cholesterol, metabolic profile, and breast cancer risk. J Natl Cancer Inst 2004, 96:1152-1160.
• [21]Zheng L, Nukuna B, Brennan ML, Sun M, Goormastic M, Settle M, Schmitt D, Fu X, Thomson L, Fox PL, et al.: Apolipoprotein A-I is a selective target for myeloperoxidase-catalyzed oxidation and functional impairment in subjects with cardiovascular disease. J Clin Invest 2004, 114:529-541.
• [22]Feng H, Li XA: Dysfunctional high-density lipoprotein. Curr Opin Endocrinol Diabetes Obes 2009, 16:156-162.
• [23]Pan B, Ren H, He Y, Lv X, Ma Y, Li J, Huang L, Yu B, Kong J, Niu C, et al.: HDL of patients with type 2 diabetes mellitus elevates the capability of promoting breast cancer metastasis. Clin Cancer Res 2012, 18:1246-1256.
• [24]Pan B, Ren H, Ma Y, Liu D, Yu B, Ji L, Pan L, Li J, Yang L, Lv X, et al.: HDL of patients with type 2 diabetes mellitus elevates the capability of promoting migration and invasion of breast cancer cells. Int J Cancer 2011, in press. doi: 10.1002/ijc.26341
• [25]Jaffe EA, Nachman RL, Becker CG, Minick CR: Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunologic criteria. J Clin Invest 1973, 52:2745-2756.
• [26]Chung BH, Wilkinson T, Geer JC, Segrest JP: Preparative and quantitative isolation of plasma lipoproteins: rapid, single discontinuous density gradient ultracentrifugation in a vertical rotor. J Lipid Res 1980, 21:284-291.
• [27]Jayaraman S, Gantz DL, Gursky O: Effects of protein oxidation on the structure and stability of model discoidal high-density lipoproteins. Biochemistry 2008, 47:3875-3882.
• [28]Gamble JR, Vadas MA: A new assay for the measurement of the attachment of neutrophils and other cell types to endothelial cells. J Immunol Methods 1988, 109:175-184.
• [29]Ratheesh A, Ingle A, Gude RP: Pentoxifylline modulates cell surface integrin expression and integrin mediated adhesion of B16F10 cells to extracellular matrix components. Cancer Biol Ther 2007, 6:1743-1752.
• [30]Kimura T, Tomura H, Mogi C, Kuwabara A, Ishiwara M, Shibasawa K, Sato K, Ohwada S, Im DS, Kurose H, et al.: Sphingosine 1-phosphate receptors mediate stimulatory and inhibitory signalings for expression of adhesion molecules in endothelial cells. Cell Signal 2006, 18:841-850.
• [31]Kang DH: Oxidative stress, DNA damage, and breast cancer. AACN Clin Issues 2002, 13:540-549.
• [32]Malins DC: Free radicals and breast cancer. Environ Health Perspect 1996, 104:1140.
• [33]Noriko NODA, Hiro WAKASUGI: Cancer and Oxidative Stress. JMAJ 2001, 44:535-539.
• [34]Guyton KZ, Kensler TW: Oxidative mechanism in carcinogenesis. Br Med Bull 1993, 49:523-544.
• [35]Boyd NF, McGuire V: The possible role of lipid peroxidation in breast cancer risk. Free Radic Biol Med 1991, 10:185-190.
• [36]Kökoğlu E, Karaarslan I, Karaarslan HM, Baloğlu H: Alterations of serum lipids and lipoproteins in breast cancer. Cancer Lett 1994, 82:175-178.
• [37]Ray G, Husain SA: Role of lipids, lipoproteins and vitamins in women with breast cancer. Clin Biochem 2001, 34:71-76.
• [38]Abu-Bedair FA, El-Gamal BA, Ibrahim NA, El-Aaser AA: Serum lipids and tissue DNA content in Egyptian female breast cancer patients. Jpn J Clin Oncol 2003, 33:278-82.
• [39]Fiorenza AM, Branchi A, Sommaviva D: Serum lipoprotein profile in patients with cancer. A comparison with non-cancer subjects. Int J Clin Lab Res 2000, 30:141-145.
• [40]Rosenson RS: Antiatherothrombotic effects of nicotinic acid. Atherosclerosis 2003, 171:87-96.
• [41]Lee CM, Chien CT, Chang PY, Hsieh MY, Jui HY, Liau CS, Hsu SM, Lee YT: High-density lipoprotein antagonizes oxidized low-density lipoprotein by suppressing oxygen free-radical formation and preserving nitric oxide bioactivity. Atherosclerosis 2005, 183:251-258.
• [42]Nicholls SJ, Dusting GJ, Cutri B, Bao S, Drummond GR, Rye KA, Barter PJ: Reconstituted high-density lipoproteins inhibit the acute pro-oxidant and proinflammatory vascular changes induced by a periarterial collar in normocholesterolemic rabbits. Circulation 2005, 111:1543-1550.