Leptin signaling molecular actions and drug target in hepatocellular carcinoma

Drug Design, Development and Therapy

Volumn 8, Issue , 2014, Pages 2295-2302

  Jiang, Nan ^a   Sun, Rongtong ^b   Sun, Qing ^c  

^a SHANDONG UNIVERSITY SCHOOL OF MEDICINE   (China)

^b WEIHAI MUNICIPAL HOSPITAL   (China)

^c THE FIRST AFFILIATED HOSPITAL OF SHANDONG FIRST MEDICAL UNIVERSITY   (China)

Author keywords

Drug target; Hepatocellular carcinoma; Leptin; Leptin antagonist; Leptin signaling; Tumor angio genesis

Indexed keywords

ALLO ACA; LEPTIN; LEPTIN RECEPTOR; MITOGEN ACTIVATED PROTEIN KINASE; MONOCLONAL ANTIBODY; MONOCLONAL ANTIBODY 9F8; PEGYLATED LEPTIN PEPTIDE RECEPTOR ANTAGONIST; PEPTIDE HORMONE RECEPTOR BLOCKING AGENT; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE B; STAT3 PROTEIN; UNCLASSIFIED DRUG; VASCULOTROPIN A; VASCULOTROPIN RECEPTOR 2;

BINDING AFFINITY; CANCER PROGNOSIS; CANCER SURVIVAL; DRUG MECHANISM; DRUG TARGETING; GENE CONTROL; HUMAN; INTRACELLULAR SIGNALING; LIVER CARCINOGENESIS; LIVER CELL CARCINOMA; NONHUMAN; OBESITY; PROTEIN DOMAIN; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN PROTEIN INTERACTION; RECEPTOR BINDING; REVIEW; SIGNAL TRANSDUCTION; TUMOR GROWTH; TUMOR INVASION; UPREGULATION; ANIMAL; ANTAGONISTS AND INHIBITORS; CARCINOMA, HEPATOCELLULAR; COMPLICATION; DRUG EFFECTS; LIVER NEOPLASMS; METABOLISM; MOLECULARLY TARGETED THERAPY;

ANIMALS; CARCINOMA, HEPATOCELLULAR; HUMANS; LEPTIN; LIVER NEOPLASMS; MOLECULAR TARGETED THERAPY; OBESITY; SIGNAL TRANSDUCTION;

EID: 84923199734     PISSN: 11778881     EISSN: 11778881     Source Type: Journal    
DOI: 10.2147/DDDT.S69004     Document Type: Review

References (124)

1. WHO. World Health Organization Fact Sheet for World Wide Prevalence of Obesity; 2006. Available from: http://www.who.int/mediacentre/factsheets/fs311/en/. Accessed November 3, 2014.
2. James WP. International association for the study of obesity and China. Obes Rev. 2008;9(suppl 1):2–3.
3. Bibiloni MD, Pons A, Tur JA. Prevalence of overweight and obesity in adolescents: a systematic review. ISRN Obes. 2013;2013:392747.
4. De Pergola G, Silvestris F. Obesity as a major risk factor for cancer. J Obes. 2013;2013:291546.
5. Baskin ML, Ard J, Franklin F, Allison DB. Prevalence of obesity in the United States. Obes Rev. 2005;6:5–7.
6. Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ, Flegal KM. Prevalence of overweight and obesity in the United States, 1999–2004. JAMA. 2006;295:1549–1555.
7. Huxley R, Mendis S, Zheleznyakov E, Reddy S, Chan J. Body mass index, waist circumference and waist:hip ratio as predictors of cardiovascular risk – a review of the literature. Eur J Clin Nutr. 2010; 64:16–22.
8. Cote AT, Harris KC, Panagiotopoulos C, Sandor GG, Devlin AM. Childhood obesity and cardiovascular dysfunction. J Am Coll Cardiol. 2013;62:1309–1319.
9. Kramer H, Dugas L, Shoham D. Obesity as an effect modifer of the risk of death in chronic kidney disease. Nephrol Dial Transplant. 2013;28(suppl 4):iv65–iv72.
10. de Vries AP, Ruggenenti P, Ruan XZ, et al; ERA-EDTA Working Group Diabesity. Fatty kidney: emerging role of ectopic lipid in obesity-related renal disease. Lancet Diabetes Endocrinol. 2014; 2:417–426.
11. Hall ME, do Carmo JM, da Silva AA, Juncos LA, Wang Z, Hall JE. Obesity, hypertension, and chronic kidney disease. Int J Nephrol Renovasc Dis. 2014;7:75–88.
12. Franssen R, Monajemi H, Stroes ES, Kastelein JJ. Obesity and dyslipi-demia. Endocrinol Metab Clin North Am. 2008;37:623–633, viii.
13. Kotsis V, Stabouli S, Papakatsika S, Rizos Z, Parati G. Mechanisms of obesity-induced hypertension. Hypertens Res. 2010;33:386–393.
14. DeMarco VG, Aroor AR, Sowers JR. The pathophysiology of hypertension in patients with obesity. Nat Rev Endocrinol. 2014; 10:364–376.
15. Cohen JC, Horton JD, Hobbs HH. Human fatty liver disease: old questions and new insights. Science. 2011;332:1519–1523.
16. Hui E, Xu A, Bo Yang H, Lam KS. Obesity as the common soil of nonalcoholic fatty liver disease and diabetes: role of adipokines. J Diabetes Investig. 2013;4:413–425.
17. Jung UJ, Choi MS. Obesity and its metabolic complications: the role of adipokines and the relationship between obesity, infammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease. Int J Mol Sci. 2014;15:6184–6223.
18. Travers ME, McCarthy MI. Type 2 diabetes and obesity: genomics and the clinic. Hum Genet. 2011;130:41–58.
19. Basen-Engquist K, Chang M. Obesity and cancer risk: recent review and evidence. Curr Oncol Rep. 2011;13:71–76.
20. Paz-Filho G, Lim EL, Wong ML, Licinio J. Associations between adipokines and obesity-related cancer. Front Biosci. 2011;16: 1634–1650.
21. Lashinger LM, Ford NA, Hursting SD. Interacting infammatory and growth factor signals underlie the obesity-cancer link. J Nutr. 2014;144:109–113.
22. Teucher B, Rohrmann S, Kaaks R. Obesity: focus on all-cause mortality and cancer. Maturitas. 2010;65:112–116.
23. Wolin KY, Carson K, Colditz GA. Obesity and cancer. Oncologist. 2010;15:556–565.
24. Han G, Zhao W, Wang L, et al. Leptin enhances the invasive ability of glioma stem-like cells depending on leptin receptor expression. Brain Res. 2014;1543:1–8.
25. Colditz GA, Wolin KY, Gehlert S. Applying what we know to accelerate cancer prevention. Sci Transl Med. 2012;4:127rv4.
26. Prieto-Hontoria PL, Perez-Matute P, Fernandez-Galilea M, Bustos M, Martinez JA, Moreno-Aliaga MJ. Role of obesity-associated dysfunctional adipose tissue in cancer: a molecular nutrition approach. Biochim Biophys Acta. 2011;1807:664–678.
27. Zhang Y, Bellows CF, Kolonin MG. Adipose tissue-derived progenitor cells and cancer. World J Stem Cells. 2010;2:103–113.
28. Kwaan HC, McMahon B. The role of plasminogen-plasmin system in cancer. Cancer Treat Res. 2009;148:43–66.
29. Khan S, Shukla S, Sinha S, Meeran SM. Role of adipokines and cytok-ines in obesity-associated breast cancer: therapeutic targets. Cytokine Growth Factor Rev. 2013;24(6):503–513.
30. Riondino S, Roselli M, Palmirotta R, Della-Morte D, Ferroni P, Guadagni F. Obesity and colorectal cancer: role of adipokines in tumor initiation and progression. World J Gastroenterol. 2014;20: 5177–5190.
31. Rogers CJ, Prabhu KS, Vijay-Kumar M. The microbiome and obe-sity-an established risk for certain types of cancer. Cancer J. 2014; 20:176–180.
32. von Scholten BJ, Andresen EN, Sorensen TI, Jess T. Aetiological factors behind adipose tissue infammation: an unexplored research area. Public Health Nutr. 2013;16:27–35.
33. Russell WR, Duncan SH, Flint HJ. The gut microbial metabolome: modulation of cancer risk in obese individuals. Proc Nutr Soc. 2013; 72:178–188.
34. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372:425–432.
35. Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet. 2008;371:569–578.
36. Polesel J, Zucchetto A, Montella M, et al. The impact of obesity and diabetes mellitus on the risk of hepatocellular carcinoma. Ann Oncol. 2009;20:353–357.
37. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003;348:1625–1638.
38. Bianchini F, Kaaks R, Vainio H. Overweight, obesity, and cancer risk. Lancet Oncol. 2002;3:565–574.
39. Larsson SC, Wolk A. Overweight, obesity and risk of liver cancer: a meta-analysis of cohort studies. Br J Cancer. 2007;97:1005–1008.
40. Sadik NA, Ahmed A, Ahmed S. The significance of serum levels of adiponectin, leptin, and hyaluronic acid in hepatocellular carcinoma of cirrhotic and noncirrhotic patients. Hum Exp Toxicol. 2012;31: 311–321.
41. Wang YY, Lin S Y. Leptin in relation to hepatocellular carcinoma in patients with liver cirrhosis. Horm Res. 2003;60:185–190.
42. Garofalo C, Surmacz E. Leptin and cancer. J Cell Physiol. 2006;207:12–22.
43. Jarde T, Perrier S, Vasson MP, Caldefie-Chezet F. Molecular mechanisms of leptin and adiponectin in breast cancer. Eur J Cancer. 2011;47:33–43.
44. Ray A, Cleary MP. Leptin as a potential therapeutic target for breast cancer prevention and treatment. Expert Opin Ther Targets. 2010;14:443–451.
45. Ribeiro R, Lopes C, Medeiros R. Leptin and prostate: implications for cancer prevention – overview of genetics and molecular interactions. Eur J Cancer Prev. 2004;13:359–368.
46. Wang SN, Lee KT, Ker CG. Leptin in hepatocellular carcinoma. World J Gastroenterol. 2010;16:5801–5809.
47. Guo S, Liu M, Wang G, Torroella-Kouri M, Gonzalez-Perez RR. Onco-genic role and therapeutic target of leptin signaling in breast cancer and cancer stem cells. Biochim Biophys Acta. 2012;1825:207–222.
48. Farooqi IS, Jebb SA, Langmack G, et al. Effects of recombinant leptin therapy in a child with congenital leptin defciency. N Engl J Med. 1999;341:879–884.
49. Halaas JL, Gajiwala KS, Maffei M, et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science. 1995;269:543–546.
50. Leinninger GM. Location, location, location: the CNS sites of leptin action dictate its regulation of homeostatic and hedonic pathways. Int J Obes (Lond). 2009;33(suppl 2):S14–S17.
51. Myers MG Jr, Munzberg H, Leinninger GM, Leshan RL. The geometry of leptin action in the brain: more complicated than a simple ARC. Cell Metab. 2009;9:117–123.
52. Robertson SA, Leinninger GM, Myers MG Jr. Molecular and neural mediators of leptin action. Physiol Behav. 2008;94:637–642.
53. Ashwin PJ, Dilipbhai PJ. Leptin and the cardiovascular system: a review. Recent Pat Cardiovasc Drug Discov. 2007;2:100–109.
54. Imagawa K, Numata Y, Katsuura G, et al. Structure-function studies of human leptin. J Biol Chem. 1998;273:35245–35249.
55. Fruhbeck G. Intracellular signalling pathways activated by leptin. Biochem J. 2006;393:7–20.
56. Friedman J. Leptin, leptin receptors, and the control of body weight. In: Blum WF, Kiess W, Rascher W, editors. Leptin – The Voice of Adipose Tissue. Heidelberg: JA Barth Verlag; 1997:3–22.
57. Tartaglia LA, Dembski M, Weng X, et al. Identification and expression cloning of a leptin receptor, OB-R. Cell. 1995;83:1263–1271.
58. Bazan JF. Structural design and molecular evolution of a cytokine receptor superfamily. Proc Natl Acad Sci U S A. 1990;87: 6934–6938.
59. Tartaglia LA. The leptin receptor. J Biol Chem. 1997;272: 6093–6096.
60. Banks AS, Davis SM, Bates SH, Myers MG Jr. Activation of downstream signals by the long form of the leptin receptor. J Biol Chem. 2000;275:14563–14572.
61. Bjorbaek C, Uotani S, da Silva B, Flier JS. Divergent signaling capacities of the long and short isoforms of the leptin receptor. J Biol Chem. 1997;272:32686–32695.
62. Stahl N, Farruggella TJ, Boulton TG, Zhong Z, Darnell JE Jr, Yancopoulos GD. Choice of STATs and other substrates specifed by modular tyrosine-based motifs in cytokine receptors. Science. 1995;267:1349–1353.
63. Wang XJ, Yuan SL, Lu Q, et al. Potential involvement of leptin in carcinogenesis of hepatocellular carcinoma. World J Gastroenterol. 2004;10:2478–2481.
64. Wang SN, Ye h YT, Yang SF, Chai CY, Lee KT. Potential role of leptin expression in hepatocellular carcinoma. J Clin Pathol. 2006;59:930–934.
65. Chen L, Shi Y, Jiang CY, Sun Q, Wang LX, Dai GH. Expression of leptin and leptin receptor in hepatocellular carcinoma and the clinico-pathological significance. Nan Fang Yi Ke Da Xue Xue Bao. 2011; 31:830–833.
66. Zhou J, Lei W, Shen L, Luo HS, Shen ZX. Primary study of leptin and human hepatocellular carcinoma in vitro. World J Gastroenterol. 2008;14:2900–2904.
67. Myers MG, Cowley MA, Munzberg H. Mechanisms of leptin action and leptin resistance. Annu Rev Physiol. 2008;70:537–556.
68. Zhou W, Tian Y, Gong H, Guo S, Luo C. Oncogenic role and therapeutic target of leptin signaling in colorectal cancer. Expert Opin Ther Targets. 2014;19:1–11.
69. Steelman LS, Stadelman KM, Chappell WH, et al. Akt as a therapeutic target in cancer. Expert Opin Ther Targets. 2008;12:1139–1165.
70. Wickenden JA, Watson CJ. Key signalling nodes in mammary gland development and cancer. Signalling downstream of PI3 kinase in mammary epithelium: a play in 3 Akts. Breast Cancer Res. 2010; 12:202.
71. Agarwal E, Brattain MG, Chowdhury S. Cell survival and metastasis regulation by Akt signaling in colorectal cancer. Cell Signal. 2013;25:1711–1719.
72. Zhou Q, Lui VW, Ye o W. Targeting the PI3K/Akt/mTOR pathway in hepatocellular carcinoma. Future Oncol. 2011;7:1149–1167.
73. Sabbah M, Emami S, Redeuilh G, et al. Molecular signature and therapeutic perspective of the epithelial-to-mesenchymal transitions in epithelial cancers. Drug Resist Updat. 2008;11:123–151.
74. Lamouille S, Derynck R. Emergence of the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin axis in transforming growth factor-beta-induced epithelial-mesenchymal transition. Cells Tissues Organs. 2011;193:8–22.
75. Fu Z, Ren L, Wei H, et al. Effects of Tyroserleutide on phosphati-dylinositol 3′-kinase/AKT pathway in human hepatocellular carcinoma cell. J Drug Target. 2014;22:146–155.
76. Cheng SP, Yin PH, Hsu YC, et al. Leptin enhances migration of human papillary thyroid cancer cells through the PI3K/AKT and MEK/ERK signaling pathways. Oncol Rep. 2011;26:1265–1271.
77. Uddin S, Bu R, Ahmed M, et al. Leptin receptor expression and its association with PI3K/AKT signaling pathway in diffuse large B-cell lymphoma. Leuk Lymphoma. 2010;51:1305–1314.
78. Uddin S, Bavi P, Siraj AK, et al. Leptin-R and its association with PI3K/AKT signaling pathway in papillary thyroid carcinoma. Endocr Relat Cancer. 2010;17:191–202.
79. Riolf M, Ferla R, Del Valle L, et al. Leptin and its receptor are over-expressed in brain tumors and correlate with the degree of malignancy. Brain Pathol. 2010;20:481–489.
80. Uddin S, Bu R, Ahmed M, et al. Overexpression of leptin receptor predicts an unfavorable outcome in Middle Eastern ovarian cancer. Mol Cancer. 2009;8:74.
81. Uddin S, Bavi PP, Hussain AR, et al. Leptin receptor expression in Middle Eastern colorectal cancer and its potential clinical implication. Carcinogenesis. 2009;30:1832–1840.
82. Shen Y, Wang Q, Zhao Q, Zhou J. Leptin promotes the immune escape of lung cancer by inducing proinfammatory cytokines and resistance to apoptosis. Mol Med Rep. 2009;2:295–299.
83. Gao J, Tian J, Lv Y, et al. Leptin induces functional activation of cyclooxygenase-2 through JAK2/STAT3, MAPK/ERK, and PI3K/ AKT pathways in human endometrial cancer cells. Cancer Sci. 2009;100:389–395.
84. Miyazaki T, Bub JD, Iwamoto Y. c-Jun NH(2)-terminal kinase mediates leptin-stimulated androgen-independent prostate cancer cell proliferation via signal transducer and activator of transcription 3 and Akt. Biochim Biophys Acta. 2008;1782:593–604.
85. Saxena NK, Sharma D, Ding X, et al. Concomitant activation of the JAK/STAT, PI3K/AKT, and ERK signaling is involved in leptin-medi-ated promotion of invasion and migration of hepatocellular carcinoma cells. Cancer Res. 2007;67:2497–2507.
86. Fletcher S, Drewry JA, Shahani VM, Page BD, Gunning PT. Molecular disruption of oncogenic signal transducer and activator of transcription 3 (STAT3) protein. Biochem Cell Biol. 2009;87:825–833.
87. Masciocchi D, Gelain A, Villa S, Meneghetti F, Barlocco D. Signal transducer and activator of transcription 3 (STAT3): a promising target for anticancer therapy. Future Med Chem. 2011;3:567–597.
88. Zhang HF, Lai R. STAT3 in cancer-friend or foe? Cancers (Basel). 2014;6:1408–1440.
89. Mankan AK, Greten FR. Inhibiting signal transducer and activator of transcription 3: rationality and rationale design of inhibitors. Expert Opin Investig Drugs. 2011;20:1263–1275.
90. Zhao M, Jiang B, Gao FH. Small molecule inhibitors of STAT3 for cancer therapy. Curr Med Chem. 2011;18(26):4012–4018.
91. Bates SH, Kulkarni RN, Seifert M, Myers MG Jr. Roles for leptin receptor/STAT3-dependent and -independent signals in the regulation of glucose homeostasis. Cell Metab. 2005;1:169–178.
92. Ratke J, Entschladen F, Niggemann B, Zanker KS, Lang K. Leptin stimulates the migration of colon carcinoma cells by multiple signaling pathways. Endocr Relat Cancer. 2010;17:179–189.
93. Catalano S, Giordano C, Rizza P, et al. Evidence that leptin through STAT and CREB signaling enhances cyclin D1 expression and promotes human endometrial cancer proliferation. J Cell Physiol. 2009;218:490–500.
94. Li L, Gao Y, Zhang LL, He DL. Concomitant activation of the JAK/ STAT3 and ERK1/2 signaling is involved in leptin-mediated proliferation of renal cell carcinoma Caki-2 cells. Cancer Biol Ther. 2008;7:1787–1792.
95. Saxena NK, Vertino PM, Anania FA, Sharma D. Leptin-induced growth stimulation of breast cancer cells involves recruitment of histone acetyltransferases and mediator complex to CYCLIN D1 promoter via activation of Stat3. J Biol Chem. 2007;282:13316–13325.
96. Pai R, Lin C, Tran T, Tarnawski A. Leptin activates STAT and ERK2 pathways and induces gastric cancer cell proliferation. Biochem Biophys Res Commun. 2005;331:984–992.
97. Yin N, Wang D, Zhang H, et al. Molecular mechanisms involved in the growth stimulation of breast cancer cells by leptin. Cancer Res. 2004;64:5870–5875.
98. Dieudonne MN, Machinal-Quelin F, Serazin-Leroy V, Leneveu MC, Pecquery R, Giudicelli Y. Leptin mediates a proliferative response in human MCF7 breast cancer cells. Biochem Biophys Res Commun. 2002;293:622–628.
99. Ogunwobi OO, Beales IL. The anti-apoptotic and growth stimulatory actions of leptin in human colon cancer cells involves activation of JNK mitogen activated protein kinase, JAK2 and PI3 kinase/Akt. IntJ Colorectal Dis. 2007;22:401–409.
100. Russo VC, Metaxas S, Kobayashi K, Harris M, Werther GA. Antiapoptotic effects of leptin in human neuroblastoma cells. Endocrinology. 2004;145:4103–4112.
101. Ren H, Zhao T, Wang X, et al. Leptin upregulates telomerase activity and transcription of human telomerase reverse transcriptase in MCF-7 breast cancer cells. Biochem Biophys Res Commun. 2010; 394:59–63.
102. Cascio S, Ferla R, D’Andrea A, et al. Expression of angiogenic regulators, VEGF and leptin, is regulated by the EGF/PI3K/STAT3 pathway in colorectal cancer cells. J Cell Physiol. 2009;221:189–194.
103. Gonzalez-Perez RR, Xu Y, Guo S, Watters A, Zhou W, Leibovich SJ. Leptin upregulates VEGF in breast cancer via canonic and non-canonical signalling pathways and NFkappaB/HIF-1alpha activation. Cell Signal. 2010;22:1350–1362.
104. Jiang H, Yu J, Guo H, Song H, Chen S. Upregulation of survivin by leptin/STAT3 signaling in MCF-7 cells. Biochem Biophys Res Commun. 2008;368:1–5.
105. Fan Y, Mao R, Yang J. NF-kappaB and STAT3 signaling pathways collaboratively link infammation to cancer. Protein Cell. 2013;4:176–185.
106. He G, Karin M. NF-kappaB and STAT3 – key players in liver infam-mation and cancer. Cell Res. 2011;21:159–168.
107. Guo S, Gonzalez-Perez RR. Notch, IL-1 and leptin crosstalk outcome (NILCO) is critical for leptin-induced proliferation, migration and VEGF/VEGFR-2 expression in breast cancer. PLoS One. 2011;6(6):e21467.
108. Zhou W, Guo S, Gonzalez-Perez RR. Leptin pro-angiogenic signature in breast cancer is linked to IL-1 signalling. Br J Cancer. 2011;104:128–137.
109. Ohba S, Lanigan TM, Roessler BJ. Leptin receptor JAK2/STAT3 signaling modulates expression of Frizzled receptors in articular chondrocytes. Osteoarthritis Cartilage. 2010;18:1620–1629.
110. Endo H, Hosono K, Uchiyama T, et al. Leptin acts as a growth factor for colorectal tumours at stages subsequent to tumour initiation in murine colon carcinogenesis. Gut. 2011;60:1363–1371.
111. Michelotti GA, Machado MV, Diehl AM. NAFLD, NASH and liver cancer. Nat Rev Gastroenterol Hepatol. 2013;10:656–665.
112. Duan XY, Zhang L, Fan JG, Qiao L. NAFLD leads to liver cancer: do we have suffcient evidence? Cancer Lett. 2014;345:230–234.
113. White DL, Kanwal F, El-Serag HB. Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol. 2012;10:1342. e2–e1359.e2.
114. Polyzos SA, Kountouras J, Zavos C, Deretzi G. The potential adverse role of leptin resistance in nonalcoholic fatty liver disease: a hypothesis based on critical review of the literature. J Clin Gastroenterol. 2011;45:50–54.
115. Ikejima K, Honda H, Yoshikawa M, et al. Leptin augments infam-matory and profbrogenic responses in the murine liver induced by hepatotoxic chemicals. Hepatology. 2001;34:288–297.
116. Aleff S, Petrai I, Bertolani C, et al. Upregulation of proinfammatory and proangiogenic cytokines by leptin in human hepatic stellate cells. Hepatology. 2005;42:1339–1348.
117. Gonzalez RR, Leavis PC. A peptide derived from the human leptin molecule is a potent inhibitor of the leptin receptor function in rabbit endometrial cells. Endocrine. 2003;21:185–195.
118. Gonzalez RR, Cherfls S, Escobar M, et al. Leptin signaling promotes the growth of mammary tumors and increases the expression of vascular endothelial growth factor (VEGF) and its receptor type two (VEGF-R2). J Biol Chem. 2006;281:26320–26328.
119. Rene Gonzalez R, Watters A, Xu Y, et al. Leptin-signaling inhibition results in effcient anti-tumor activity in estrogen receptor positive or negative breast cancer. Breast Cancer Res. 2009;11:R36.
120. Otvos L Jr, Kovalszky I, Riolf M, et al. Efficacy of a leptin receptor antagonist peptide in a mouse model of triple-negative breast cancer. Eur J Cancer. 2011;47:1578–1584.
121. Beccari S, Kovalszky I, Wade JD, Otvos L Jr, Surmacz E. Designer peptide antagonist of the leptin receptor with peripheral antineoplastic activity. Peptides. 2013;44:127–134.
122. Zabeau L, Verhee A, Catteeuw D, et al. Selection of non-competitive leptin antagonists using a random nanobody-based approach. Biochem J. 2012;441:425–434.
123. Fazeli M, Zarkesh-Esfahani H, Wu Z, et al. Identification of a monoclonal antibody against the leptin receptor that acts as an antagonist and blocks human monocyte and T cell activation. J Immunol Methods. 2006;312:190–200.
124. Carpenter B, Hemsworth GR, Wu Z, et al. Structure of the human obesity receptor leptin-binding domain reveals the mechanism of leptin antagonism by a monoclonal antibody. Structure. 2012;20:487–497.