Oncostatin M treatment increases the responsiveness toward cisplatin‑based chemoradiotherapy in cervical cancer cells in a STAT3‑dependent manner

Stroeder,Russalina; Walch‑Rückheim,Barbara; Fischbach,Jil; Juhasz‑Böss,Ingolf; Rübe,Christian; Solomayer,Erich‑Franz; Smola,Sigrun

doi:10.3892/ol.2018.8987

Oncostatin M treatment increases the responsiveness toward cisplatin‑based chemoradiotherapy in cervical cancer cells in a STAT3‑dependent manner

Authors:
- Russalina Stroeder
- Barbara Walch‑Rückheim
- Jil Fischbach
- Ingolf Juhasz‑Böss
- Christian Rübe
- Erich‑Franz Solomayer
- Sigrun Smola
View Affiliations

Affiliations: Department of Gynecology and Obstetrics, Saarland University, D‑66421 Homburg/Saar, Germany, Institute of Virology, Saarland University, D‑66421 Homburg/Saar, Germany, Department of Radiotherapy and Radiation Oncology, Saarland University, D‑66421 Homburg/Saar, Germany
Published online on: June 18, 2018 https://doi.org/10.3892/ol.2018.8987
Pages: 3351-3358

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

Cervical cancer stage‑dependent therapies include surgery, chemotherapy, radiotherapy and chemoradiotherapy. Concurrent cisplatin‑based chemoradiotherapy (CCRT) is the standard therapy for locally advanced cervical carcinoma (FIGO>IIB), however therapy resistance in a subset of patients is still a major clinical challenge. The present study aimed to analyze the impact of Oncostatin M (OSM) stimulation on CCRT‑induced cell death. The present study used cells derived from cervical squamous cell carcinomas (SW756, 808, CaSki and 879) and adenocarcinoma (HeLa). The cervical carcinoma cells were HPV18‑positive (HeLa, SW756, 808) or HPV16‑positive (CaSki, 879). In addition to the established cell lines HeLa, SW756 and CaSki, the more recently generated cervical cancer cells 808 and 879 were also used. To analyze their radiosensitivity, cells were treated with increasing doses of irradiation (0‑8 Gy). To mimic chemotherapy, radiotherapy or CCRT in vitro, the cells were challenged with 0.975 µg/ml cisplatin, irradiated with 6 Gy or a combination. A total of 10 ng/ml OSM was applied for 2 h prior to the respective therapy. The responsiveness toward radiation alone varied among the cervical carcinoma cells. CaSki, 808 and 879 cells were resistant to irradiation up to 8 Gy. OSM pre‑treatment sensitized two out of five cell lines (HeLa and 879) to irradiation. Notably, all tested cells were sensitized by OSM for CCRT‑treatment, particularly in the less radiosensitive cells. Cell death enhancement was dependent on phosphorylated signal transducer and activator of transcription 3 (STAT3; Tyr705) signaling activation as demonstrated with a dominant‑negative version of STAT3 interfering with phosphorylation at Tyr705 (dnSTAT3‑Y705F). In conclusion, OSM pre‑treatment was able to override resistance to CCRT via the STAT3 signaling pathway.

View Figures

View References

1	Hausen Zur H: Papillomaviruses in the causation of human cancers-a brief historical account. Virology. 384:260–265. 2009. View Article : Google Scholar : PubMed/NCBI
2	Barillot I, Horiot JC, Pigneux J, Schraub S, Pourquier H, Daly N, Bolla M and Rozan R: Carcinoma of the intact uterine cervix treated with radiotherapy alone: A French cooperative study: Update and multivariate analysis of prognostics factors. Int J Radiat Oncol Biol Phys. 38:969–978. 1997. View Article : Google Scholar : PubMed/NCBI
3	Logsdon MD and Eifel PJ: Figo IIIB squamous cell carcinoma of the cervix: An analysis of prognostic factors emphasizing the balance between external beam and intracavitary radiation therapy. Int J Radiat Oncol Biol Phys. 43:763–775. 1999. View Article : Google Scholar : PubMed/NCBI
4	Perez CA, Camel HM, Kuske RR, Kao MS, Galakatos A, Hederman MA and Powers WE: Radiation therapy alone in the treatment of carcinoma of the uterine cervix: A 20-year experience. Gynecol Oncol. 23:127–140. 1986. View Article : Google Scholar : PubMed/NCBI
5	Monk BJ, Tewari KS and Koh WJ: Multimodality therapy for locally advanced cervical carcinoma: State of the art and future directions. J Clin Oncol. 25:2952–2965. 2007. View Article : Google Scholar : PubMed/NCBI
6	Morris M, Eifel PJ, Lu J, Grigsby PW, Levenback C, Stevens RE, Rotman M, Gershenson DM and Mutch DG: Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med. 340:1137–1143. 1999. View Article : Google Scholar : PubMed/NCBI
7	Keys HM, Bundy BN, Stehman FB, Muderspach LI, Chafe WE, Suggs CL III, Walker JL and Gersell D: Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med. 340:1154–1161. 1999. View Article : Google Scholar : PubMed/NCBI
8	Rose PG, Bundy BN, Watkins EB, Thigpen JT, Deppe G, Maiman MA, Clarke-Pearson DL and Insalaco S: Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med. 340:1144–1153. 1999. View Article : Google Scholar : PubMed/NCBI
9	Peltenburg LT: Radiosensitivity of tumor cells. Oncogenes and apoptosis. Q J Nucl Med. 44:355–364. 2000.PubMed/NCBI
10	Walch-Ruckheim B, Pahne-Zeppenfeld J, Fischbach J, Wickenhauser C, Horn LC, Tharun L, Büttner R, Mallmann P, Stern P, Kim YJ, et al: STAT3/IRF1 Pathway activation sensitizes cervical cancer cells to chemotherapeutic drugs. Cancer Res. 76:3872–3883. 2016. View Article : Google Scholar : PubMed/NCBI
11	Taniguchi K and Karin M: IL-6 and related cytokines as the critical lynchpins between inflammation and cancer. Semin Immunol. 26:54–74. 2014. View Article : Google Scholar : PubMed/NCBI
12	Nakajima K, Yamanaka Y, Nakae K, Kojima H, Ichiba M, Kiuchi N, Kitaoka T, Fukada T, Hibi M and Hirano T: A central role for Stat3 in IL-6-induced regulation of growth and differentiation in M1 leukemia cells. Embo J. 15:3651–3658. 1996.PubMed/NCBI
13	Wei LH, Kuo ML, Chen CA, Chou CH, Cheng WF, Chang MC, Su JL and Hsieh CY: The anti-apoptotic role of interleukin-6 in human cervical cancer is mediated by up-regulation of Mcl-1 through a PI 3-K/Akt pathway. Oncogene. 20:5799–5809. 2001. View Article : Google Scholar : PubMed/NCBI
14	Jee SH, Chiu HC, Tsai TF, Tsai WL, Liao YH, Chu CY and Kuo ML: The phosphotidyl inositol 3-kinase/Akt signal pathway is involved in interleukin-6-mediated Mcl-1 upregulation and anti-apoptosis activity in basal cell carcinoma cells. J Invest Dermatol. 119:1121–1127. 2002. View Article : Google Scholar : PubMed/NCBI
15	Chen CL, Hsieh FC, Lieblein JC, Brown J, Chan C, Wallace JA, Cheng G, Hall BM and Lin J: Stat3 activation in human endometrial and cervical cancers. Br J Cancer. 96:591–599. 2007. View Article : Google Scholar : PubMed/NCBI
16	Pattillo RA, Hussa RO, Story MT, Ruckert AC, Shalaby MR and Mattingly RF: Tumor antigen and human chorionic gonadotropin in CaSki cells: A new epidermoid cervical cancer cell line. Science. 196:1456–1458. 1977. View Article : Google Scholar : PubMed/NCBI
17	Freedman RS, Bowen JM, Leibovitz A, Pathak S, Siciliano MJ, Gallager HS and Giovanella BC: Characterization of a cell line (SW756) derived from a human squamous carcinoma of the uterine cervix. In vitro. 18:719–726. 1982. View Article : Google Scholar : PubMed/NCBI
18	Jones HW Jr, McKusick VA, Harper PS and Wuu KD: George Otto Gey. (1899–1970). The HeLa cell and a reappraisal of its origin. Obstet Gynecol. 38:945–949. 1971.PubMed/NCBI
19	Brady CS, Bartholomew JS, Burt DJ, Duggan-Keen MF, Glenville S, Telford N, Little AM, Davidson JA, Jimenez P, Ruiz-Cabello F, et al: Multiple mechanisms underlie HLA dysregulation in cervical cancer. Tissue Antigens. 55:401–411. 2000. View Article : Google Scholar : PubMed/NCBI
20	Vanneman M and Dranoff G: Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer. 12:237–251. 2012. View Article : Google Scholar : PubMed/NCBI
21	Hughes PE, Caenepeel S and Wu LC: Targeted therapy and checkpoint immunotherapy combinations for the treatment of cancer. Trends Immunol. 37:462–476. 2016. View Article : Google Scholar : PubMed/NCBI
22	Melero I, Berman DM, Aznar MA, Korman AJ, Gracia Pérez JL and Haanen J: Evolving synergistic combinations of targeted immunotherapies to combat cancer. Nat Rev Cancer. 15:457–472. 2015. View Article : Google Scholar : PubMed/NCBI
23	Sharma P and Allison JP: The future of immune checkpoint therapy. Science. 348:56–61. 2015. View Article : Google Scholar : PubMed/NCBI
24	Sharma P and Allison JP: Immune checkpoint targeting in cancer therapy: Toward combination strategies with curative potential. Cell. 161:205–214. 2015. View Article : Google Scholar : PubMed/NCBI
25	Topalian SL, Drake CG and Pardoll DM: Immune checkpoint blockade: A common denominator approach to cancer therapy. Cancer Cell. 27:450–461. 2015. View Article : Google Scholar : PubMed/NCBI
26	Tewari KS, Sill MW, Long HJ III, Penson RT, Huang H, Ramondetta LM, Landrum LM, Oaknin A, Reid TJ, Leitao MM, et al: Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med. 370:734–743. 2014. View Article : Google Scholar : PubMed/NCBI
27	Tsuda N, Watari H and Ushijima K: Chemotherapy and molecular targeting therapy for recurrent cervical cancer. Chin J Cancer Res. 28:241–253. 2016. View Article : Google Scholar : PubMed/NCBI
28	Karim R, Meyers C, Backendorf C, Ludigs K, Offringa R, van Ommen GJ, Melief CJ, van der Burg SH and Boer JM: Human papillomavirus deregulates the response of a cellular network comprising of chemotactic and proinflammatory genes. PLoS One. 6:e178482011. View Article : Google Scholar : PubMed/NCBI
29	Schroer N, Pahne J, Walch B, Wickenhauser C and Smola S: Molecular pathobiology of human cervical high-grade lesions: Paracrine STAT3 activation in tumor-instructed myeloid cells drives local MMP-9 expression. Cancer Res. 71:87–97. 2011. View Article : Google Scholar : PubMed/NCBI
30	Pahne-Zeppenfeld J, Schröer N, Walch-Rückheim B, Oldak M, Gorter A, Hegde S and Smola S: Cervical cancer cell-derived interleukin-6 impairs CCR7-dependent migration of MMP-9 expressing dendritic cells. Int J Cancer. 134:2061–2073. 2014. View Article : Google Scholar : PubMed/NCBI
31	Walch-Rückheim B, Mavrova R, Henning M, Vicinus B, Kim YJ, Bohle RM, Juhasz-Böss I, Solomayer EF and Smola S: Stromal fibroblasts induce CCL20 through IL6/C/EBPbeta to support the recruitment of Th17 cells during cervical cancer progression. Cancer Res. 75:5248–5259. 2015. View Article : Google Scholar : PubMed/NCBI
32	Heusinkveld M, de Vos van Steenwijk PJ, Goedemans R, Ramwadhdoebe TH, Gorter A, Welters MJ, van Hall T and van der Burg SH: M2 macrophages induced by prostaglandin E2 and IL-6 from cervical carcinoma are switched to activated M1 macrophages by CD4+ Th1 cells. J Immunol. 187:1157–1165. 2011. View Article : Google Scholar : PubMed/NCBI
33	Zijlmans HJ, Punt S, Fleuren GJ, Trimbos JB, Kenter GG and Gorter A: Role of IL-12p40 in cervical carcinoma. Br J Cancer. 107:1956–1962. 2012. View Article : Google Scholar : PubMed/NCBI
34	Schmidt SV, Seibert S, Walch-Rückheim B, Vicinus B, Kamionka EM, Pahne-Zeppenfeld J, Solomayer EF, Kim YJ, Bohle RM and Smola S: RIPK3 expression in cervical cancer cells is required for PolyIC-induced necroptosis, IL-1α release and efficient paracrine dendritic cell activation. Oncotarget. 6:8635–8647. 2015. View Article : Google Scholar : PubMed/NCBI
35	Smola S: RIPK3-a predictive marker for personalized immunotherapy? Oncoimmunology. 5:e10756952015. View Article : Google Scholar : PubMed/NCBI
36	Tanaka M and Miyajima A: Oncostatin M, a multifunctional cytokine. Rev Physiol Biochem Pharmacol. 149:39–52. 2003. View Article : Google Scholar : PubMed/NCBI
37	Winder DM, Chattopadhyay A, Muralidhar B, Bauer J, English WR, Zhang X, Karagavriilidou K, Roberts I, Pett MR, Murphy G and Coleman N: Overexpression of the oncostatin M receptor in cervical squamous cell carcinoma cells is associated with a pro-angiogenic phenotype and increased cell motility and invasiveness. J Pathol. 225:448–462. 2011. View Article : Google Scholar : PubMed/NCBI
38	Caffarel MM and Coleman N: Oncostatin M receptor is a novel therapeutic target in cervical squamous cell carcinoma. J Pathol. 232:386–390. 2014. View Article : Google Scholar : PubMed/NCBI
39	Kucia-Tran JA, Tulkki V, Smith S, Scarpini CG, Hughes K, Araujo AM, Yan KY, Botthof J, Pérez-Gómez E, Quintanilla M, et al: Overexpression of the oncostatin-M receptor in cervical squamous cell carcinoma is associated with epithelial-mesenchymal transition and poor overall survival. Br J Cancer. 115:212–222. 2016. View Article : Google Scholar : PubMed/NCBI