Login Register Cart 0
Generic placeholder image

Current Pharmaceutical Biotechnology

Editor-in-Chief

ISSN (Print): 1389-2010
ISSN (Online): 1873-4316

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

Evaluation of Variances in VEGF-A-D and VEGFR-1-3 Expression in the Ishikawa Endometrial Cancer Cell Line Treated with Salinomycin and Anti-Angiogenic/Lymphangiogenic Effect

Author(s): Piotr Kras*, Karol Talkowski, Beniamin O. Grabarek, Nina Skalska-Dziobek, Dariusz Boroń and Marcin Oplawski

Volume 22, Issue 5, 2021

Published on: 10 July, 2020

Page: [697 - 705] Pages: 9

DOI: 10.2174/1389201021666200710093519

Price: $65

Abstract

Background: In cancer, an excessive and uncontrolled process of creating new blood and lymphatic vessels that play a key role in the metastasis process can be observed. The Vascular Endothelial Growth Factor (VEGF-A,-B,-C,-D) family together with their specific receptors (VEGFR-1,-2,- 3) plays a key role in these processes, therefore, it would be reasonable to determine the correct pattern of their expression.

Objectives: The study aimed to assess the use of salinomycin as an anti-angiogenic and anti-lymphangiogenic drug during endometrial cancer by examining changes in the expression pattern of VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGFR-1, VEGFR-2 and VEGFR-3 depending on the treatment period of the Ishikawa endometrial cancer cells with salinomycin in comparison to the control culture.

Materials and Methods: To determine how influential salinomycin was on the expression of both mRNAs, 1 μM of the drug was added to the cell culture and then it was cultured all together for 12, 24 and 48 hour periods. The cells that made up the control culture were not treated with salinomycin. To determine the changes in the expression profile of the selected genes, we used the microarray, techniques: RTqPCR and ELISA (p<0.05).

Results: For all isoforms of VEGF-A-D as well as receptors of VEGFR-1-3, a decrease in expression under the influence of salinomycin was noted. For VEGF-A and VEGFR-1, the difference in the expression between the culture treated with salinomycin in comparison to the control was statistically significant (p=0.0004). In turn, for VEGF-B, the difference between the culture exposed for 24 hours in comparison to the control (p=0.00000) as well as the comparison between H48 vs. C (p=0.00000) was statistically significant. In reference to VEGF-C, VEGFR-2 and VEGFR-3, the statistical analysis showed the significant difference in expression between the culture incubated with the drug for 12, 24 and 48 hours in comparison to the control as well as between the selected times. For all of these comparisons, p=0.00000 was utilized.

Conclusion: Salinomycin changes the expression pattern of VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGFR-1, VEGFR-2, and VEGFR-3 in endometrial cancer cells. The obtained results suggest that salinomycin might exert the effect via VEGF signaling pathways.

Keywords: Salinomycin, angiogenesis, lymphangiogenesis, anti-angiogenic and anti-lymphangiogenic endometrial cancer`s drug, molecular diagnostic.

« Previous Next »
Graphical Abstract

[1]
Zuazo-Gaztelu, I.; Casanovas, O. Unraveling the role of angiogenesis in cancer ecosystems. Front. Oncol., 2018, 8, 248.
[http://dx.doi.org/10.3389/fonc.2018.00248] [PMID: 30013950]
[2]
Rajabi, M.; Mousa, S.A. The role of angiogenesis in cancer treatment. Biomedicines, 2017, 5(2), 34.
[http://dx.doi.org/10.3390/biomedicines5020034] [PMID: 28635679]
[3]
Liang, G.; Liu, Z.; Tan, L.; Su, A.N.; Jiang, W.G.; Gong, C. HIF1α-associated circDENND4C promotes proliferation of breast cancer cells in hypoxic environment. Anticancer Res., 2017, 37(8), 4337-4343.
[PMID: 28739726]
[4]
Guo, J.Y.; White, E. Autophagy metabolism and cancer In Cold Spring Harbor symposia on quantitative biology. Cold Spring Harbor Laboratory Press, 2016, 81, 73-78.
[5]
Bhandari, V.; Hoey, C.; Liu, L.Y.; Lalonde, E.; Ray, J.; Livingstone, J.; Lesurf, R.; Shiah, Y.J.; Vujcic, T.; Huang, X.; Espiritu, S.M.G.; Heisler, L.E.; Yousif, F.; Huang, V.; Yamaguchi, T.N.; Yao, C.Q.; Sabelnykova, V.Y.; Fraser, M.; Chua, M.L.K.; van der Kwast, T.; Liu, S.K.; Boutros, P.C.; Bristow, R.G. Molecular landmarks of tumor hypoxia across cancer types. Nat. Genet., 2019, 51(2), 308-318.
[http://dx.doi.org/10.1038/s41588-018-0318-2] [PMID: 30643250]
[6]
Alhazzani, K.; Alaseem, A.; Algahtani, M.; Dhandayuthapani, S.; Venkatesan, T.; Rathinavelu, A. angiogenesis in cancer treatment 60 years’ swing between promising trials and disappointing tribulations anti-angiogenesis. Drug Discov. Devel., 2019, 4, 434.
[7]
Ribatti, D. Epithelial-mesenchymal transition in morphogenesis, cancer progression and angiogenesis. Exp. Cell Res., 2017, 353(1), 1-5.
[http://dx.doi.org/10.1016/j.yexcr.2017.02.041] [PMID: 28257786]
[8]
Hisada, Y.; Mackman, N. Tissue Factor and Cancer Regulation Tumor Growth and Metastasis.Seminars in thrombosis and hemostasis; Thieme Medical Publishers, 2019, pp. 454385-454395.
[http://dx.doi.org/10.1055/s-0039-1687894]
[9]
Skobe, M.; Pytowski, B. Significance and Molecular Regulation of Lymphangiogenesis in Cancer Tumor Angiogenesis A Key Target for Cancer Therapy; Springer, 2019, pp. 157-159.
[http://dx.doi.org/10.1007/978-3-319-33673-2_51]
[10]
Schito, L. Hypoxia and cancer metastasis. hypoxia-dependent angiogenesis and lymphangiogenesis in cancer. Adv. Exp. Med. Biol., 2019, 1136, 71-85.
[11]
Paduch, R. The role of lymphangiogenesis and angiogenesis in tumor metastasis. Cell Oncol. (Dordr.), 2016, 39(5), 397-410.
[http://dx.doi.org/10.1007/s13402-016-0281-9] [PMID: 27126599]
[12]
Tseng, H.S.; Chen, L.S.; Kuo, S.J.; Chen, S.T.; Wang, Y.F.; Chen, D.R. Tumor characteristics of breast cancer in predicting axillary lymph node metastasis. Med. Sci. Res., 2014, 20, 1155.
[13]
Shibuya, M.; Claesson-Welsh, L. Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis. Exp. Cell Res., 2006, 312(5), 549-560.
[http://dx.doi.org/10.1016/j.yexcr.2005.11.012] [PMID: 16336962]
[14]
Lohela, M.; Bry, M.; Tammela, T.; Alitalo, K. VEGFs and receptors involved in angiogenesis versus lymphangiogenesis. Curr. Opin. Cell Biol., 2009, 21(2), 154-165.
[http://dx.doi.org/10.1016/j.ceb.2008.12.012] [PMID: 19230644]
[15]
Sznurkowski, J.J.; Knapp, P.; Bodnar, L.; Bidziński, M.; Jach, R.; Misiek, M.; Markowska, J. Zalecenia, P.; Towarzystwa, G. Oncology department regarding the diagnosis and treatment of endometrial cancer. Curr. Gynecol. Oncol, 2017, 151, 34-44.
[http://dx.doi.org/10.15557/CGO.2017.0003]
[16]
Gruber, M.; Handle, F.; Culig, Z. The stem cell inhibitor salinomycin decreases colony formation potential and tumor-initiating population in docetaxel-sensitive and docetaxel-resistant prostate cancer cells. Prostate, 2020, 80(3), 267-273.
[http://dx.doi.org/10.1002/pros.23940] [PMID: 31834633]
[17]
Dewangan, J.; Srivastava, S.; Rath, S.K. Salinomycin: A new paradigm in cancer therapy. Tumour Biol., 2017, 39(3)1010428317695035
[http://dx.doi.org/10.1177/1010428317695035] [PMID: 28349817]
[18]
Kusunoki, S.; Kato, K.; Tabu, K.; Inagaki, T.; Okabe, H.; Kaneda, H.; Suga, S.; Terao, Y.; Taga, T.; Takeda, S. The inhibitory effect of salinomycin on the proliferation, migration and invasion of human endometrial cancer stem-like cells. Gynecol. Oncol., 2013, 129(3), 598-605.
[http://dx.doi.org/10.1016/j.ygyno.2013.03.005] [PMID: 23500085]
[19]
Ge, Y.L.; Zhang, X.; Zhang, J.Y.; Hou, L.; Tian, R.H. The mechanisms on apoptosis by inhibiting VEGF expression in human breast cancer cells. Int. Immunopharmacol., 2009, 9(4), 389-395.
[http://dx.doi.org/10.1016/j.intimp.2008.11.020] [PMID: 19162240]
[20]
Fuchs, D.; Heinold, A.; Opelz, G.; Daniel, V.; Naujokat, C. Salinomycin induces apoptosis and overcomes apoptosis resistance in human cancer cells. Biochem. Biophys. Res. Commun., 2009, 390(3), 743-749.
[http://dx.doi.org/10.1016/j.bbrc.2009.10.042] [PMID: 19835841]
[21]
Chung, H.; Kim, Y.H.; Kwon, M.; Shin, S.J.; Kwon, S.H.; Cha, S.D.; Cho, C.H. The effect of salinomycin on ovarian cancer stem-like cells. Obstet. Gynecol. Sci., 2016, 59(4), 261-268.
[http://dx.doi.org/10.5468/ogs.2016.59.4.261] [PMID: 27462592]
[22]
Gupta, P.B.; Onder, T.T.; Jiang, G.; Tao, K.; Kuperwasser, C.; Weinberg, R.A.; Lander, E.S. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell, 2009, 138(4), 645-659.
[http://dx.doi.org/10.1016/j.cell.2009.06.034] [PMID: 19682730]
[23]
Lessey, B.A.; Ilesanmi, A.O.; Castelbaum, A.J.; Yuan, L.; Somkuti, S.G.; Chwalisz, K.; Satyaswaroop, P.G. Characterization of the functional progesterone receptor in an endometrial adenocarcinoma cell line (Ishikawa): progesterone-induced expression of the α1 integrin. J. Steroid Biochem. Mol. Biol., 1996, 59(1), 31-39.
[http://dx.doi.org/10.1016/S0960-0760(96)00103-3] [PMID: 9009235]
[24]
Dewangan, J.; Srivastava, S.; Mishra, S.; Divakar, A.; Kumar, S.; Rath, S.K. Salinomycin inhibits breast cancer progression via targeting HIF-1α/VEGF mediated tumor angiogenesis in vitro and in vivo. Biochem. Pharmacol., 2019, 164, 326-335.
[http://dx.doi.org/10.1016/j.bcp.2019.04.026] [PMID: 31028743]
[25]
Li, T.; Liu, X.; Shen, Q.; Yang, W.; Huo, Z.; Liu, Q.; Jiao, H.; Chen, J. Salinomycin exerts anti-angiogenic and anti-tumorigenic activities by inhibiting vascular endothelial growth factor receptor 2-mediated angiogenesis. Oncotarget, 2016, 7(18), 26580-26592.
[http://dx.doi.org/10.18632/oncotarget.8555] [PMID: 27058891]
[26]
Wang, J.; Taylor, A.; Showeil, R.; Trivedi, P.; Horimoto, Y.; Bagwan, I.; Ewington, L.; Lam, E.W.; El-Bahrawy, M.A. Expression profiling and significance of VEGF-A, VEGFR2, VEGFR3 and related proteins in endometrial carcinoma. Cytokine, 2014, 68(2), 94-100.
[http://dx.doi.org/10.1016/j.cyto.2014.04.005] [PMID: 24845798]
[27]
Doi, Y.; Yashiro, M.; Yamada, N.; Amano, R.; Noda, S.; Hirakawa, K. VEGF-A/VEGFR-2 signaling plays an important role for the motility of pancreas cancer cells. Ann. Surg. Oncol., 2012, 19(8), 2733-2743.
[http://dx.doi.org/10.1245/s10434-011-2181-6] [PMID: 22207048]
[28]
Bi, Y.L.; Mi, P.Y.; Zhao, S.J.; Pan, H.M.; Li, H.J.; Liu, F.; Shao, L.R.; Zhang, H.F.; Zhang, P.; Jiang, S.L. Salinomycin exhibits anti-angiogenic activity against human glioma in vitro and in vivo by suppressing the VEGF-VEGFR2-AKT/FAK signaling axis. Int. J. Mol. Med., 2017, 39(5), 1255-1261.
[http://dx.doi.org/10.3892/ijmm.2017.2940] [PMID: 28358414]
[29]
Chen, R.; Lee, C.; Lin, X.; Zhao, C.; Li, X. Novel function of VEGF-B as an antioxidant and therapeutic implications. Pharmacol. Res., 2019, 143, 33-39.
[http://dx.doi.org/10.1016/j.phrs.2019.03.002] [PMID: 30851357]
[30]
Li, C.; Zheng, J.; Xue, Y. Effects of vascular endothelial growth factor and epidermal growth factor on biological properties of gastric cancer cells. Arch. Med. Sci., 2019, 15(6), 1498-1509.
[http://dx.doi.org/10.5114/aoms.2019.88443] [PMID: 31749879]
[31]
Hanrahan, V.; Currie, M.J.; Gunningham, S.P.; Morrin, H.R.; Scott, P.A.; Robinson, B.A.; Fox, S.B. The angiogenic switch for vascular endothelial growth factor (VEGF)-A, VEGF-B, VEGF-C, and VEGF-D in the adenoma-carcinoma sequence during colorectal cancer progression. J. Pathol., 2003, 200(2), 183-194.
[http://dx.doi.org/10.1002/path.1339] [PMID: 12754739]
[32]
Hari, A.; Vegi, N.; Das, U. Arachidonic and eicosapentaenoic acids induce oxidative stress to suppress proliferation of human glioma cells. Arch. Med. Sci., 2020. 16(4), 974-983.
[http://dx.doi.org/10.5114/aoms.2020.92293]
[33]
Muramatsu, M.; Yamamoto, S.; Osawa, T.; Shibuya, M. Vascular endothelial growth factor receptor-1 signaling promotes mobilization of macrophage lineage cells from bone marrow and stimulates solid tumor growth. Cancer Res., 2010, 70(20), 8211-8221.
[http://dx.doi.org/10.1158/0008-5472.CAN-10-0202] [PMID: 20924106]
[34]
Atzori, M.G.; Ceci, C.; Ruffini, F.; Trapani, M.; Barbaccia, M.L.; Tentori, L.; D’Atri, S.; Lacal, P.M.; Graziani, G. Role of VEGFR-1 in melanoma acquired resistance to the BRAF inhibitor vemurafenib. J. Cell. Mol. Med., 2020, 24(1), 465-475.
[http://dx.doi.org/10.1111/jcmm.14755] [PMID: 31758648]
[35]
Sopo, M.; Anttila, M.; Hämäläinen, K.; Kivelä, A.; Ylä-Herttuala, S. Kosma. V.M.; Sallinen, H. Expression profiles of VEGF-A VEGF-D and VEGFR1 are higher in distant metastases than in matched primary high grade epithelial ovarian cancer. BMC Cancer, 2019, 191, 584.
[http://dx.doi.org/10.1186/s12885-019-5757-3] [PMID: 31200683]
[36]
Zajkowska, M.; Lubowicka, E.; Fiedorowicz, W.; Szmitkowski, M.; Jamiołkowski, J.; Ławicki, S. Human Plasma Levels of VEGF-A, VEGF-C, VEGF-D, their Soluble Receptor - VEGFR-2 and Applicability of these Parameters as Tumor Markers in the Diagnostics of Breast Cancer. Pathol. Oncol. Res., 2019, 25(4), 1477-1486.
[http://dx.doi.org/10.1007/s12253-018-0527-0] [PMID: 30387014]
[37]
Bruno, V.; Corrado, G.; Baci, D.; Chiofalo, B.; Carosi, M.A.; Ronchetti, L.; Piccione, E.; Albini, A.; Noonan, D.M.; Piaggio, G.; Vizza, E. Endometrial Cancer Immune Escape Mechanisms: Let Us Learn From the Fetal-Maternal Interface. Front. Oncol., 2020, 10, 156.
[http://dx.doi.org/10.3389/fonc.2020.00156] [PMID: 32226771]
[38]
Park, Y.G.; Choi, J.; Jung, H.K.; Song, I.K.; Shin, Y.; Park, S.Y.; Seol, J.W. Fluid shear stress regulates vascular remodeling via VEGFR-3 activation, although independently of its ligand, VEGF-C, in the uterus during pregnancy. Int. J. Mol. Med., 2017, 40(4), 1210-1216.
[http://dx.doi.org/10.3892/ijmm.2017.3108] [PMID: 28849193]
[39]
Dziobek, K.; Opławski, M.; Grabarek, B.O.; Zmarzły, N.; Tomala, B.; Halski, T.; Leśniak, E.; Januszyk, K.; Brus, R.; Kiełbasiński, R.; Boroń, D. Changes in the Expression Profile of VEGF-A, VEGF-B, VEGFR-1, VEGFR-2 in Different Grades of Endometrial Cancer. Curr. Pharm. Biotechnol., 2019, 20(11), 955-963.
[http://dx.doi.org/10.2174/1389201020666190717092448] [PMID: 31322068]
[40]
Oplawski, M.; Dziobek, K.; Zmarzły, N.; Grabarek, B. Halski, T.; Januszyk, P.; Boroń, D. Expression Profile of VEGF-C VEGF-D and VEGFR-3 in Different Grades of Endometrial Cancer. Curr. Pharm. Biotechnol., 2019, 20(12), 1004-1010.
[http://dx.doi.org/10.2174/1389201020666190718164431] [PMID: 31333122]

Rights & Permissions Print Cite
Article Metrics
19
1
© 2024 Bentham Science Publishers | Privacy Policy