Login Register Cart 0
Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Receptor Binding Inhibitor Suppresses Carcinogenesis of Cervical Cancer by Depressing Levels of FSHR and ERβ in Mice

Author(s): Zhuandi Gong, Xiaoyun Shen, Juan Yang, Luju Lai and Suocheng Wei*

Volume 19, Issue 14, 2019

Page: [1719 - 1727] Pages: 9

DOI: 10.2174/1871520619666190801094059

Price: $65

Abstract

Background: FSH Receptor Binding Inhibitor (FRBI) blocked the binding of FSH to FSHR. Our initial study revealed FRBI reduced the maturation rate, enhanced the apoptosis of sheep Cumulus-Oocyte Complex (COCs). Little is known about whether FRBI modulates ERβ and FSHR levels in the normal uterine and cancerous tissues. The present study aimed to evaluate the FRBI effects on the expressions of Estrogen Receptor-beta (ERβ) and FSH receptor (FSHR) in the uteri.

Methods: 150 mice were assigned to FRBI+FSH (COM), FSH and control groups (CG). Mice of COM-1, COM-2 and COM-3 groups were simultaneously intramuscularly injected with 500, 750 and 1000 µg FRBI with 10 IU FSH, respectively for five days. Western blotting and qPCR were utilized to determine the expression of ERβ and FSHR.

Results: In comparison with FSH group, uterine lumen and glands of COM groups became narrow. The uterine wall and endometrial epithelium were thinned, and uterine lumen became narrow. Epithelial cells were decreased. Uterine wall thicknesses of COM-1, COM-2 and COM-3 groups were reduced by 6.49%, 14.89% and 15.69% on day 30 as compared with FSH group. Uterine perimetrium thicknesses of COM-1, COM-2 and COM-3 groups were reduced by 16.17%, 17.93% and 19.92% on day 20 in comparison with FSH group. Levels of FSHR mRNAs and proteins of COM-1, COM-2 and COM-3 groups were less than FSH group on days 20 and 30 (P<0.05). ERβ protein of COM-3 group was less than FSH group. Serum estradiol (E2) and FSH concentrations of COM-2 and COM-3 were lower than that of FSH group on day 30.

Conclusion: FRBI could decrease UWT and UPT, also block the uterine development, decline expression levels of ERβ and FSHR protein. Additionally, FRBI reduced the secretion of secretion of FSH and E2. Downregulating expression of FSHR and ERβ may be a potential treatment regimen for cervical cancer patients.

Keywords: Uterine cancer, follicle stimulating hormone receptor, FSH receptor binding inhibitor, estrogen receptor, estradiol, mice.

« Previous Next »
Graphical Abstract

[1]
Lin, A.J.; Hassanzadeh, C.; Markovina, S.; Schwarz, J.; Grigsby, P. Brachytherapy and survival in small cell cancer of the cervix and uterus. Brachytherapy, 2018, 18(2), 163-170.
[2]
Bermudez, A.; Bhatla, N.; Leung, E. Cancer of the cervix uteri. Int. J. Gynaecol. Obstet., 2015, 131(Suppl. 2), S88-S95.
[3]
Ponikwicka-Tyszko, D.; Chrusciel, M.; Stelmaszewska, J.; Bernaczyk, P.; Sztachelska, M.; Sidorkiewicz, I.; Doroszko, M.; Tomaszewski, J.; Tapanainen, J.S.; Huhtaniemi, I.; Wolczynski, S.; Rahman, N.A. Functional expression of FSH receptor in endometriotic lesions. J. Clin. Endocrinol. Metab., 2016, 101(7), 2905-2914.
[4]
Zidi, S.; Stayoussef, M.; Alsaleh, B.L.; Gazouani, E.; Mezlini, A.; Ebrahim, B.H.; Yacoubi-Loueslati, B.; Almawi, W.Y. Effect of follicle stimulating hormone receptor gene polymorphisms in cervical cancer risk. Pathol. Oncol. Res., 2017, 23, 565-572.
[5]
Chitnis, S.S.; Selvaakumar, C.; Jagtap, D.D.; Barnwal, R.P.; Chary, K.V.; Mahale, S.D.; Nandedkar, T.D. Interaction of follicle-stimulating hormone (FSH) receptor binding inhibitor-8: A novel FSH-binding inhibitor, with FSH and its receptor. Chem. Biol. Drug Des., 2009, 73(6), 637-643.
[6]
Wei, S.; Guo, H.; Gong, Z.; Zhang, F.; Ma, Z. Triptorelin and cetrorelix induce immune responses and affect uterine development and expressions of genes and proteins of ESR1, LHR, and FSHR of mice. Immunopharmacol. Immunotoxicol., 2016, 38(3), 197-204.
[7]
Heldring, N.; Pike, A.; Andersson, S.; Matthews, J.; Cheng, G.; Hartman, J.; Tujague, M.; Ström, A.; Treuter, E.; Warner, M.; Gustafsson, J-A. Estrogen receptors: How do they signal and what are their targets. Physiol. Rev., 2007, 87(3), 905-931.
[8]
Yaşar, P.; Ayaz, G.; User, S.D.; Güpür, G.; Muyan, M. Molecular mechanism of estrogen-estrogen receptor signaling. Reprod. Med. Biol., 2016, 16(1), 4-20.
[9]
Bronowicka-Klys, D.E.; Lianeri, M.; Jagodzinski, P.P. The role and impact of estrogens and xenoestrogen on the development of cervical cancer. Biomed. Pharmacother., 2016, 84, 1945-1953.
[10]
Wei, S.; Gong, Z.; An, L.; Zhang, T.; Zhang, F.; Chen, S. Cetrorelix and Triptorelin active immunization influences follicle development and receptor expressions of ovaries in mice. J. Appl. Biomed., 2016, 14, 49.
[11]
Lalic, N.; Perin, B.; Secen, N.; Sazdanic, D. PUB117 beta estrogen receptor as potential prognostic factor in lung adenocarcinoma. J. Thorac. Oncol., 2017, 12, S1515.
[12]
Warner, M.; Huang, B.; Gustafsson, J.A. Estrogen receptor beta as a pharmaceutical target. Trends Pharmacol. Sci., 2017, 38, 92.
[13]
Lakshminarasimhan, R.; Andreu-Vieyra, C.; Lawrenson, K.; Duymich, C.E.; Gayther, S.A.; Liang, G.; Jones, P.A. Down-regulation of ARID1A is sufficient to initiate neoplastic transformation along with epigenetic reprogramming in non-tumorigenic endometriotic cells. Cancer Lett., 2017, 401, 11-19.
[14]
Lin, Y.F.; Tseng, I.J.; Kuo, C.J.; Lin, H.Y.; Chiu, I.J.; Chiu, H.W. High level expression of ARID1A predicts a favourable outcome in triple negative breast cancer patients receiving paclitaxel based chemotherapy. J. Cell. Mol. Med., 2018, 22(4), 2458-2468.
[15]
Wadia, P.R.; Mahale, S.D.; Nandedkar, T.D. Effect of the human follicle-stimulating hormone-binding inhibitor and its N-terminal fragment on follicle-stimulating hormone-induced progesterone secretion by granulosa cells in vitro. J. Biosci., 2007, 32(6), 1185-1194.
[16]
Wei, S.; Shen, X.; Gong, Z.; Deng, Y.; Lai, L.; Liang, H. FSHR and LHR expression and signaling as well as maturation and apoptosis of cumulus-oocyte complexes following treatment with FSH receptor binding inhibitor in sheep. Cell. Physiol. Biochem., 2017, 43, 660.
[17]
Zhang, L.; Wang, C.; Yu, S.; Jia, C.; Yan, J.; Lu, Z.; Chen, J. Loss of ARID1A expression correlates with tumor differentiation and tumor progression stage in pancreatic ductal adenocarcinoma. Technol. Cancer Res. Treat., 2018, 17 1533034618754475
[18]
Donaubauer, E.M.; Law, N.C.; Hunzicker-Dunn, M.E. Follicle-Stimulating Hormone (FSH)-dependent regulation of Extracellular Regulated Kinase (ERK) phosphorylation by the Mitogen-activated Protein (MAP) kinase phosphatase MKP3. J. Biol. Chem., 2016, 291(37), 19701-19712.
[19]
Mahmood, S.; Fahimeh, K. Determination of FSH-receptor antagonistic property of 6-amino-4-phenyltetrahydroquinoline derivatives by employing QSDAR method. Phys. Chem., 2014, 9, 1.
[20]
Zhuandi, G.; Tuanjie, C.; Luju, L.; Abdiryim, A.; Yingying, D.; Haoqin, L.; Suocheng, W.; Li, D. FSH receptor binding inhibitor restrains follicular development and possibly attenuates carcinogenesis of ovarian cancer through down-regulating expression levels of FSHR and ERβ in normal ovarian tissues. Gene, 2018, 668, 174-181.
[21]
Zhuandi, G.; Haoqin, L.; Yingying, D.; Luju, L.; Suocheng, W.; Yingpai, Z.; You, L. FSH receptor binding inhibitor influences estrogen production, receptor expression and signal pathway during in vitro maturation of sheep COCs. Theriogenology, 2017, 101, 144-150.
[22]
Wei, S.; Chen, S.; Gong, Z.; Ouyang, X.; An, L.; Xie, K.; Dong, J.; Wei, M. Alarelin active immunization influences expression levels of GnRHR, FSHR and LHR proteins in the ovary and enhances follicular development in ewes. Animal. Sci. J., 2013, 84(6), 466-475.
[23]
Rajshri, M.N.; Dhanashree, D.; Jagtap, S.U.; Nayak, T.D.N.; Smita, D.M. Chem. Biol. Drug Des., 2013, 82(2), 178-188.
[24]
Bazer, F.W.; Burghardt, R.C.; Johnson, G.A.; Spencer, T.E.; Wu, G. Interferons and progesterone for establishment and maintenance of pregnancy: Interactions among novel cell signaling pathways. Reprod. Biol., 2008, 8(3), 179-211.
[25]
Wei, S.; Gong, Z.; An, L.; Zhang, T.; Dai, H.; Chen, S. Cloprostenol and pregnant mare serum gonadotropin promote estrus synchronization, uterine development, and follicle-stimulating hormone receptor expression in mice. Genetics. Mol. Res., 2015, 14, 7184-7195.
[26]
Sacchi, S.; Sena, P.; Degli Esposti, C.; Lui, J.; La Marca, A. Evidence for expression and functionality of FSH and LH/hCG receptors in human endometrium. J. Assist. Reprod. Genet., 2018, 35(9), 1703-1712.
[27]
Verena, K.; Ivanka, Z.; Sabine, H.; Fabinshy, T.; Klaus, F.; Doris, M.; Udo, J. ESR1 promoter methylation in squamous cell cervical cancer. Anticancer Res., 2014, 34, 723-727.
[28]
Schüler-Toprak, S.; Moehle, C.; Skrzypczak, M.; Ortmann, O.; Treeck, O. Effect of estrogen receptor β agonists on proliferation and gene expression of ovarian cancer cells. BMC Cancer, 2017, 17(1), 319.
[29]
Adurthi, S.; Kumar, M.M.; Vinodkumar, H.S.; Mukherjee, G.; Krishnamurthy, H.; Acharya, K.K.; Bafna, U.D.; Uma, D.K.; Abhishekh, B.; Krishna, S.; Parchure, A.; Alka, M.; Jayshree, R.S. Oestrogen Receptor-α binds the FOXP3 promoter and modulates regulatory T-cell function in human cervical cancer. Sci. Rep., 2017, 7, 17289.
[30]
Yu, P.; Wang, Y.; Li, C.; Lv, L.; Wang, J. Protective effects of downregulating estrogen receptor alpha expression in cervical cancer. Anticancer. Agents Med. Chem., 2018, 18(14), 1975-1982.
[31]
Sullivan, R.R.; Faris, B.R.; Eborn, D.; Grieger, D.M.; Cino-Ozuna, A.G.; Rozell, T.G. Follicular expression of follicle stimulating hormone receptor variants in the ewe. Reprod. Biol. Endocrinol., 2013, 11, 113.
[32]
Detti, L.; Saed, G.M.; Fletcher, N.M.; Kruger, M.L.; Brossoit, M.; Diamond, M.P. Endometrial morphology and modulation of hormone receptors during ovarian stimulation for assisted reproductive technology cycles. Fertil. Steril., 2011, 95(3), 1037-1041.
[33]
Piketty, V.; Kara, E.; Guillou, F.; Reiter, E.; Crepieux, P. Follicle-stimulating hormone (FSH) activates extracellular signal-regulated kinase phosphorylation independently of beta-arrestin- and dynamin-mediated FSH receptor internalization. Reproduct. Biol. Endocrinol., 2006, 4, 33.
[34]
Navalakhe, R.M.; Jagtap, D.D.; Nayak, S.U.; Nandedkar, T.D.; Mahale, S.D. Effect of FSH receptor-binding inhibitor-8 on FSH mediated granulosa cell signaling and proliferation. Chem. Biol. Drug Des., 2013, 82, 178-188.

Rights & Permissions Print Cite
Article Metrics
46
1
© 2024 Bentham Science Publishers | Privacy Policy