Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 3/2016

Open Access 01-09-2016 | Original Article

The molecular mechanism of action of superactive human leptin antagonist (SHLA) and quadruple leptin mutein Lan-2 on human ovarian epithelial cell lines

Authors: Elżbieta Fiedor, Ewa Łucja Gregoraszczuk

Published in: Cancer Chemotherapy and Pharmacology | Issue 3/2016

Login to get access

Abstract

Introduction

A number of leptin receptor antagonists have been synthesised for therapeutic use, with pre-clinical tests suggesting their future use in anticancer therapy. To our knowledge, there are no data concerning the possible application of leptin receptor blockers in ovarian cancer.

Methods

In this study, we evaluated two leptin receptor antagonists: superactive human leptin antagonist (SHLA) and quadruple leptin mutein, Lan-2 (L39A/D40A/F41A/I42A), on cell proliferation (Alamar Blue test, BrdU assay), cell cycle gene (qPCR) and protein expression (Western blot) and cell signalling pathways (Western blot) in three different types of cell lines: OVCAR-3, CaOV-3 and HOSEpiC.

Results

Both receptor blockers had no effect on non-cancerous HOSEpiC cell line proliferation; however, both reversed the stimulatory effect of leptin on CaOV-3 cell line proliferation to control levels and to below control levels in OVCAR-3 cells. In metastatic carcinoma CaOV-3, both ObR antagonists had an inhibitory effect on the cdk2/cyclin D1 complex, while in serous carcinoma, OVCAR-3, they only had an effect on cdk2 and cdk4 protein expression. SHLA had an inhibitory effect on all investigated signalling pathways in OVCAR-3, while only on Stat3 in CaOV-3. Lan-2 had an inhibitory effect on Stat3 and ERK1/2 in CaOV-3, while in OVCAR-3 it only affected Akt protein phosphorylation.

Conclusion

Based on these results, we conclude that SHLA and Lan-2 are promising leptin receptor inhibitors which could be used to block leptin activity, eliminating its negative effects on activities related to carcinogenesis. However, the selection of a specific antagonist should be related to tumour type.
Literature
1.
Choi JH, Park SH, Leung PC, Choi KC (2005) Expression of leptin receptors and potential effects of leptin on the cell growth and activation of mitogen-activated protein kinases in ovarian cancer cells. J Clin Endocrinol Metab 90:207–210CrossRefPubMed
2.
Ptak A, Kolaczkowska E, Gregoraszczuk EL (2013) Leptin stimulation of cell cycle and inhibition of apoptosis gene and protein expression in ovcar-3 ovarian cancer cells. Endocrine 43:394–403CrossRefPubMed
3.
Cuello-Fredes M, Kato S, Abarzúa-Catalán L, Delpiano A. Trigo C, García K, Sanhueza C, Ibañez C, Brañes J, Castellon E, Owen G (2015) Leptin promotes a more aggressive behavior of ovarian cancer cells: a potential explanation for a worse prognosis in obese. Int J Gynecol Cancer 25(Suppl1):67
4.
Leitzmann MF, Koebnick C, Danforth KN, Brinton LA, Moore SC, Hollenbeck AR, Schatzkin A, Lacey JV Jr (2009) Body mass index and risk of ovarian cancer. Cancer 15:812–822CrossRef
5.
Owecki M, Nikisch E, Miczke A, Pupek-Musialik D, Sowiński J (2010) Leptin, soluble leptin receptors, free leptin index, and their relationship with insulin resistance and BMI: high normal BMI is the threshold for serum leptin increase in humans. Horm Metab Res 42:585–589CrossRefPubMed
6.
Silha JV, Krsek M, Skrha JV, Sucharda P, Nyomba BL, Murphy LJ (2003) Plasma resistin, adiponectin and leptin levels in lean and obese subjects: correlations with insulin resistance. Eur J Endocrinol 149:331–335CrossRefPubMed
7.
Olsen CM, Green AC, Whiteman DC, Sadeghi S, Kolahdooz F, Webb PM (2007) Obesity and the risk of epithelial ovarian cancer: a systematic review and meta-analysis. Eur J Cancer 43:690–709CrossRefPubMed
8.
Uddin S, Bu R, Ahmed M, Abubaker J, Al-Dayel F, Bavi P, Al-Kuraya KS (2009) Overexpression of leptin receptor predicts an unfavorable outcome in Middle Eastern ovarian cancer. Mol Cancer 18(8):74CrossRef
9.
10.
Somasundar P, Yu AK, Vona-Davis L, McFadden DW (2003) Differential effects of leptin on cancer in vitro. J Surg Res 113:50–55CrossRefPubMed
11.
Hu X, Juneja SC, Maihle NJ, Cleary MP (2002) Leptin–a growth factor in normal and malignant breast cells and for normal mammary gland development. J Natl Cancer Inst 94:1704–1711CrossRefPubMed
12.
Zhang B, Cai FF, Zhong XY (2011) An overview of biomarkers for the ovarian cancer diagnosis. Eur J Obstet Gynecol Reprod Biol 158:119–123CrossRefPubMed
13.
Chen C, Chang YC, Lan MS, Breslin M (2013) Leptin stimulates ovarian cancer cell growth and inhibits apoptosis by increasing cyclin D1 and Mcl-1 expression via the activation of the MEK/ERK1/2 and PI3 K/Akt signaling pathways. Int J Oncol 42:1113–1119PubMed
14.
Gertler A, Solomon G (2013) Leptin-activity blockers: development and potential use in experimental biology and medicine. Can J Physiol Pharmacol 91:873–882CrossRefPubMed
15.
Otvos L Jr, Kovalszky I, Riolfi M, Ferla R, Olah J, Sztodola A, Nama K, Molino A, Piubello Q, Wade JD, Surmacz E (2011) Efficacy of a leptin receptor antagonist peptide in a mouse model of triple-negative breast cancer. Eur J Cancer 47:1578–1584CrossRefPubMed
16.
Catalano S, Leggio A, Barone I, De Marco R, Gelsomino L, Campana A, Malivindi R, Panza S, Giordano C, Liguori A, Bonofiglio D, Liguori A, Andò S (2015) A novel leptin antagonist peptide inhibits breast cancer growth in vitro and in vivo. J Cell Mol Med 19:1122–1132CrossRefPubMedPubMedCentral
17.
Samuel-Mendelsohn S, Inbar M, Weiss-Messer E, Niv-Spector L, Gertler A, Barkey RJ (2001) Leptin signaling and apoptotic effects in human prostate cancer cell lines. Prostate 71:929–945CrossRef
18.
Bain GH, Collie-Duguid E, Murray GI, Gilbert FJ, Denison A, Mckiddie F, Ahearn T, Fleming I, Leeds J, Phull P, Park K, Nanthakumaran S, Grabsch HI, Tan P, Welch A, Schweiger L, Dahle-Smith A, Urquhart G, Finegan M, Matula KM, Petty RD (2015) Tumour expression of leptin is associated with chemotherapy resistance and therapy-independent prognosis in gastro-oesophageal adenocarcinomas. Br J Cancer 113:1641CrossRefPubMedPubMedCentral
19.
Gregoraszczuk EL, Rak A (2015) Superactive human leptin antagonist reverses leptin-induced excessive progesterone and testosterone secretion in porcine ovarian follicles by blocking leptin receptors. J Physiol Pharmacol 66:39–46PubMed
20.
Di Yorio MP, Bilbao MG, Pustovrh MC, Prestifilippo JP, Faletti AG (2008) Leptin modulates the expression of its receptors in the hypothalamic-pituitary-ovarian axis in a differential way. J Endocrinol 198(2):355–366CrossRefPubMed
21.
Gao J, Tian J, Lv Y, Shi F, Kong F, Shi H, Zhao L (2009) Leptin induces functional activation of cyclooxygenase-2 through JAK2/STAT3, MAPK/ERK, and PI3 K/AKT pathways in human endometrial cancer cells. Cancer Sci 100:389–395CrossRefPubMed
22.
Ishikawa M, Kitayama J, Nagawa H (2004) Enhanced expression of leptin and leptin receptor (OB-R) in human breast cancer. Clin Cancer Res 10:4325–4331CrossRefPubMed
23.
Laud K, Gourdou I, Pessemesse L, Peyrat JP, Djiane J (2002) Identification of leptin receptors in human breast cancer: functional activity in the T47-D breast cancer cell line. Mol Cell Endocrinol 188:219–226CrossRefPubMed
24.
Yin N, Wang D, Zhang H, Yi X, Sun X, Shi B, Wu H, Wu G, Wang X, Shang Y (2004) Molecular mechanisms involved in the growth stimulation of breast cancer cells by leptin. Cancer Res 64:5870–5875CrossRefPubMed
25.
Garofalo C, Sisci D, Surmacz E (2004) Leptin interferes with the effects of the antiestrogen ICI 182,780 in MCF-7 breast cancer cells. Clin Cancer Res 10:6466–6475CrossRefPubMed
26.
Briscoe CP, Hanif S, Arch JR, Tadayyon M (2001) Leptin receptor long-form signaling in a human liver cell line. Cytokine 14:225–229CrossRefPubMed
27.
Hardwick JC, Van Den Brink GR, Offerhaus GJ, Van Deventer SJ, Peppelenbosch MP (2001) Leptin is a growth factor for colonic epithelial cells. Gastroenterology 121:79–90CrossRefPubMed
28.
Otvos L Jr, Kovalszky I, Scolaro L, Sztodola A, Olah J, Cassone M, Knappe D, Hoffmann R, Lovas S, Hatfield MP, Beko G, Zhang S, Wade JD, Surmacz E (2011) Peptide-based leptin receptor antagonists for cancer treatment and appetite regulation. Biopolymers 96:117–125CrossRefPubMed
29.
Beccari S, Kovalszky I, Wade JD, Otvos L Jr, Surmacz E (2013) Designer peptide antagonist of the leptin receptor with peripheral antineoplastic activity. Peptides 44:127–134CrossRefPubMed
30.
31.
Chen C, Chang YC, Liu CL, Chang KJ, Guo IC (2006) Leptin-induced growth of human ZR-75-1 breast cancer cells is associated with up-regulation of cyclin D1 and c-Myc and down-regulation of tumor suppressor p53 and p21WAF1/CIP1. Breast Cancer Res Treat 98:121–132CrossRefPubMed
32.
Saxena NK, Vertino PM, Anania FA, Sharma D (2007) 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 282:13316–13325CrossRefPubMedPubMedCentral
33.
Catalano S, Giordano C, Rizza P, Gu G, Barone I, Bonofiglio D, Giordano F, Malivindi R, Gaccione D, Lanzino M, De Amicis F, Andò S (2009) Evidence that leptin through STAT and CREB signaling enhances cyclin D1 expression and promotes human endometrial cancer proliferation. J Cell Physiol 218:490–500CrossRefPubMed
34.
Rouet-Benzineb P, Aparicio T, Guilmeau S, Pouzet C, Descatoire V, Buyse M, Bado A (2004) Leptin counteracts sodium butyrate-induced apoptosis in human colon cancer HT-29 cells via NF-kappaB signaling. J Biol Chem 279:16495–16502CrossRefPubMed
35.
Chen C, Chang YC, Liu CL, Liu TP, Chang KJ, Guo IC (2007) Leptin induces proliferation and anti-apoptosis in human hepatocarcinoma cells by up-regulating cyclin D1 and down-regulating Bax via a Janus kinase 2-linked pathway. Endocr Relat Cancer 14:513–529CrossRefPubMed
36.
Reimer D, Sadr S, Wiedemair A, Stadlmann S, Concin N, Hofstetter G, Müller-Holzner E, Marth C, Zeimet AG (2007) Clinical relevance of E2F family members in ovarian cancer–an evaluation in a training set of 77 patients. Clin Cancer Res 13:144–151CrossRef
37.
Suh DS, Yoon MS, Choi KU, Kim JY (2008) Significance of E2F-1 overexpression in epithelial ovarian cancer. Int J Gynecol Cancer 18:492–498CrossRef
38.
Masamha CP, Benbrook DM (2009) Cyclin D1 degradation is sufficient to induce G1 cell cycle arrest despite constitutive expression of cyclin E2 in ovarian cancer cells. Cancer Res 69:6565–6572CrossRefPubMed
39.
Somasundar P, Frankenberry KA, Skinner H, Vedula G, McFadden DW, Riggs D, Jackson B, Vangilder R, Hileman SM, Vona-Davis LC (2004) Prostate cancer cell proliferation is influenced by leptin. J Surg Res 118:71–82CrossRefPubMed
40.
Ogunwobi OO, Beales IL (2007) 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. Int J Colorectal Dis 22:401–409CrossRefPubMed
Metadata
Title
The molecular mechanism of action of superactive human leptin antagonist (SHLA) and quadruple leptin mutein Lan-2 on human ovarian epithelial cell lines
Authors
Elżbieta Fiedor
Ewa Łucja Gregoraszczuk
Publication date
01-09-2016
Publisher
Springer Berlin Heidelberg
Published in
Cancer Chemotherapy and Pharmacology / Issue 3/2016
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-016-3113-8

Other articles of this Issue 3/2016

Cancer Chemotherapy and Pharmacology 3/2016 Go to the issue

Original Article

Myelosuppression by chemotherapy in obese patients with gynecological cancers

Editorial

Editorial

Original Article

Effects of a bolus injection of 5-fluorouracil on dihydropyrimidine dehydrogenase activity in rats receiving continuous infusion of 5-fluorouracil

Original Article

Phase 1 study to evaluate the effect of the MEK inhibitor trametinib on cardiac repolarization in patients with solid tumours

Original Article

Model-based prediction of progression-free survival in patients with first-line renal cell carcinoma using week 8 tumor size change from baseline

Original Article

SM-1, a novel PAC-1 derivative, activates procaspase-3 and causes cancer cell apoptosis
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits