Erythropoietin promotes expression of survivin via STAT3 activation and reduces sensitivity to cisplatin in cervical cancer cells

Vázquez‑Mellado,María José; Cortés‑Ballinas,Liliana Guadalupe; Blanco‑Flores,Irma Carolina; Aguilar,Cecilia; Vázquez‑Gómez,Gerardo; Rocha‑Zavaleta,Leticia

doi:10.3892/or.2018.6890

Erythropoietin promotes expression of survivin via STAT3 activation and reduces sensitivity to cisplatin in cervical cancer cells

Authors:
- María José Vázquez‑Mellado
- Liliana Guadalupe Cortés‑Ballinas
- Irma Carolina Blanco‑Flores
- Cecilia Aguilar
- Gerardo Vázquez‑Gómez
- Leticia Rocha‑Zavaleta
View Affiliations

Affiliations: Departamento de Biología Molecular y Biotecnología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Circuito Escolar S/N, Ciudad Universitaria, Coyoacán, Ciudad de México 04510, México, Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Circuito Escolar S/N, Ciudad Universitaria, Coyoacán, Ciudad de México 04510, México
Published online on: November 27, 2018 https://doi.org/10.3892/or.2018.6890
Pages: 1333-1341

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Erythropoietin (Epo) is used for the treatment of cancer‑associated anaemia. However, certain studies have identified that the administration of Epo mediates the acquisition of resistance to cisplatin, which is widely used to treat cervical cancer. Our group previously reported that cervical cancer cells express Epo receptor and that exogenous Epo induces cell proliferation and migration. However, the effect of Epo on cervical cancer cell death mediated by chemotherapeutic agents has not yet been evaluated. Thus, the aim of the present study was to assess the potential effect of Epo on the cytotoxic activity of cisplatin in cervical cancer cells. The effect of Epo was assessed in 3 cervical cancer‑derived cell lines. It was observed that pre‑incubation with Epo induced a significant reduction of cisplatin‑induced apoptosis in vitro and in vivo. Incubation with Epo induced the expression and activation of the transcriptional factor signal transducer and activator of transcription 3 (STAT3), which in turn stimulated the expression and activation of the anti‑apoptotic protein survivin. The cytotoxicity of cisplatin was partially restored by treating the cells with MY155, an inhibitor of survivin. Conversely, inhibition of STAT3 activation using sub‑lethal doses of WP1066, completely abolished the cytoprotective effect of Epo. These observations indicated that Epo was able to hinder the cytotoxic effect of cisplatin in cervical cancer cells by activating anti‑apoptotic responses regulated by STAT3.

View Figures

View References

1	Weiss G and Goodnough LT: Anemia of chronic disease. N Engl J Med. 352:1011–1023. 2005. View Article : Google Scholar : PubMed/NCBI
2	Steegmann JL, Sanchez Torres JM, Colomer R, Vaz A, Lopez J, Jalon I, Provencio M, Gonzalez-Martin A and Perez M: Prevalence and management of anaemia in patients with non-myeloid cancer undergoing systemic therapy: A Spanish survey. Clin Transl Oncol. 15:477–483. 2013. View Article : Google Scholar : PubMed/NCBI
3	Szenajch J, Wcislo G, Jeong JY, Szczylik C and Feldman L: The role of erythropoietin and its receptor in growth, survival and therapeutic response of human tumor cells from clinic to bench-A critical review. Biochim Biophys Acta. 1806:82–95. 2010.PubMed/NCBI
4	Marti HH: Erythropoietin and the hypoxic brain. J Exp Biol. 207:3233–3242. 2004. View Article : Google Scholar : PubMed/NCBI
5	Wang Y, Zhang H, Liu Y, Li P, Cao Z and Cao Y: Erythropoietin (EPO) protects against high glucose-induced apoptosis in retinal ganglional cells. Cell Biochem Biophys. 71:749–755. 2015. View Article : Google Scholar : PubMed/NCBI
6	Pezeshki Z, Nematbakhsh M, Mazaheri S, Eshraghi-Jazi F, Talebi A, Nasri H, Safari T, Mansouri A and Ashrafi F: Estrogen abolishes protective effect of erythropoietin against cisplatin-induced nephrotoxicity in ovariectomized rats. SRN Oncol. 2012:8903102012.
7	Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136:E359–E386. 2015. View Article : Google Scholar : PubMed/NCBI
8	Candelaria M, Cetina L and Dueñas-Gonzalez A: Anemia in cervical cancer patients. Implications for iron supplementation therapy. Med Oncol. 22:161–168. 2005. View Article : Google Scholar : PubMed/NCBI
9	Lopez TV, Lappin TR, Maxwell P, Shi Z, Lopez-Marure R, Aguilar C and Rocha-Zavaleta L: Autocrine/paracrine erythropoietin signalling promotes JAK/STAT-dependent proliferation of human cervical cancer cells. Int J Cancer. 129:2566–2576. 2011. View Article : Google Scholar : PubMed/NCBI
10	Aguilar C, Aguilar C, Lopez-Marure R, Jimenez-Sanchez A and Rocha-Zavaleta L: Co-stimulation with stem cell factor and erythropoietin enhances migration of c-kit expressing cervical cancer cells through the sustained activation of ERK1/2. Mol Med Rep. 9:1895–1902. 2014. View Article : Google Scholar : PubMed/NCBI
11	Hamadmad SN and Hohl RJ: Lovastatin suppresses erythropoietin receptor surface expression through dual inhibition of glycosylation and geranylgeranylation. Biochem Pharmacol. 74:590–600. 2007. View Article : Google Scholar : PubMed/NCBI
12	Fukada T, Hibi M, Yamanaka Y, Takahashi-Tezuka M, Fujitani Y, Yamaguchi T, Nakajima K and Hirano T: Two signals are necessary for cell proliferation induced by a cytokine receptor gp130: Involvement of STAT3 in anti-apoptosis. Immunity. 5:449–460. 1996. View Article : Google Scholar : PubMed/NCBI
13	Gu L, Chiang KY, Zhu N, Findley HW and Zhou M: Contribution of STAT3 to the activation of survivin by GM-CSF in CD34⁺ cell lines. Exp Hematol. 35:957–966. 2007. View Article : Google Scholar : PubMed/NCBI
14	O'Connor DS, Grossman D, Plescia J, Li F, Zhang H, Villa A, Tognin S, Marchisio PC and Altieri DC: Regulation of apoptosis at cell division by p34^cdc2 phosphorylation of survivin. Proc Natl Acad Sci USA. 97:13103131072000. View Article : Google Scholar
15	Wall NR, O'Connor DS, Plescia J, Pommier Y and Altieri DC: Suppression of survivin phosphorylation on Thr34 by flavopiridol enhances tumor cell apoptosis. Cancer Res. 63:230–235. 2003.PubMed/NCBI
16	Judd LM, Menheniott TR, Ling H, Jackson CB, Howlett M, Kalantzis A, Priebe W and Giraud AS: Inhibition of the JAK2/STAT3 pathway reduces gastric cancer growth in vitro and in vivo. PLoS One. 9:e959932014. View Article : Google Scholar : PubMed/NCBI
17	Nakahara T, Kita A, Yamanaka K, Mori M, Amino N, Takeuchi M, Tominaga F, Hatakeyama S, Kinoyama I, Matsuhisa A, et al: YM155, a novel small-molecule survivin suppressant, induces regression of established human hormone-refractory prostate tumor xenografts. Cancer Res. 67:8014–8021. 2007. View Article : Google Scholar : PubMed/NCBI
18	Alural B, Ayyildiz ZO, Tufekci KU, Genc S and Genc K: Erythropoietin promotes glioblastoma via miRNA-451 suppression. Vitam Horm. 105:249–271. 2017. View Article : Google Scholar : PubMed/NCBI
19	Merkle R, Steiert B, Salopiata F, Depner S, Raue A, Iwamoto N, Schelker M, Hass H, Wasch M, Bohm ME, et al: Identification of cell type-specific differences in erythropoietin receptor signalling in primary erythroid and lung cancer cells. PLoS Comput Biol. 12:e10050492016. View Article : Google Scholar : PubMed/NCBI
20	Zhu H, Luo H, Zhang W, Shen Z, Hu X and Zhu X: Molecular mechanisms of cisplatin resistance in cervical cancer. Drug Des Devel Ther. 10:1885–1895. 2016. View Article : Google Scholar : PubMed/NCBI
21	Ding Z, Yang X, Pater A and Tang SC: Resistance to apoptosis is correlated with the reduced caspase-3 activation and enhanced expression of antiapoptotic proteins in human cervical multidrug-resistant cells. Biochem Biophys Res Commun. 270:415–420. 2000. View Article : Google Scholar : PubMed/NCBI
22	Lai SY, Childs EE, Xi S, Coppelli FM, Gooding WE, Wells A, Ferris RL and Grandis JR: Erythropoietin-mediated activation of JAK-STAT signaling contributes to cellular invasion in head and neck squamous cell carcinoma. Oncogene. 24:4442–4449. 2005. View Article : Google Scholar : PubMed/NCBI
23	Shi Z, Hodges VM, Dunlop EA, Percy MJ, Maxwell AP, El-Tanani M and Lappin TR: Erythropoietin-induced activation of the JAK2/STAT5, PI3K/Akt, and Ras/ERK pathways promotes malignant cell behaviour in a modified breast cancer cell line. Mol Cancer Res. 8:615–626. 2010. View Article : Google Scholar : PubMed/NCBI
24	Yu H, Lee H, Herrmann A, Buettner R and Jove R: Revisiting STAT3 signalling in cancer: New and unexpected biological functions. Nat Rev Cancer. 14:736–746. 2014. View Article : Google Scholar : PubMed/NCBI
25	Wei S, Luo C, Yu S, Gao J, Liu C, Wei Z, Zhang Z, Wei L and Yi B: Erythropoietin ameliorates early brain injury after subarachnoid haemorrage by modulating microglia polarization via the EPOR/JAK2-STAT3 pathway. Exp Cell Res. 361:342–352. 2017. View Article : Google Scholar : PubMed/NCBI
26	Gritsko T, Williams A, Turkson J, Kaneko S, Bowman T, Huang M, Nam S, Eweis I, Diaz N, Sullivan D, et al: Persistent activation of STAT3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells. Clin Cancer Res. 12:11–19. 2006. View Article : Google Scholar : PubMed/NCBI
27	Hu W, Jin P and Liu W: Periostin contributes to cisplatin resistance in human non-small cell lung cancer A549 cells via activation of Stat3 and Akt and upregulation on survivin. Cell Physiol Biochem. 38:1199–1208. 2016. View Article : Google Scholar : PubMed/NCBI
28	Altieri DC: Survivin, cancer networks and pathway-directed drug discovery. Nat Rev Cancer. 8:61–70. 2008. View Article : Google Scholar : PubMed/NCBI
29	Fan Y and Chen J: Clinicopathological significance of survivin expression in patients with cervical cancer: A systematic meta-analysis. Bioengineered. 8:511–523. 2017. View Article : Google Scholar : PubMed/NCBI