Inhibition of GP130/STAT3 and EMT by combined bazedoxifene and paclitaxel treatment in ovarian cancer

Park,Sun-Ae; Kim,Lee Kyung; Park,Hye Min; Kim,Hee Jung; Heo,Tae-Hwe

doi:10.3892/or.2022.8263

Inhibition of GP130/STAT3 and EMT by combined bazedoxifene and paclitaxel treatment in ovarian cancer

Authors:
- Sun-Ae Park
- Lee Kyung Kim
- Hye Min Park
- Hee Jung Kim
- Tae-Hwe Heo
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Affiliations: Laboratory of Pharmacoimmunology, Integrated Research Institute of Pharmaceutical Sciences and BK21 FOUR Team for Advanced Program for Smart Pharma Leaders, College of Pharmacy, The Catholic University of Korea, Bucheon‑si, Gyeonggi‑do 14662, Republic of Korea
Published online on: January 13, 2022 https://doi.org/10.3892/or.2022.8263
Article Number: 52
Copyright: © Park et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The interleukin 6 (IL‑6)/glycoprotein 130 (GP130)/signal transducer and activator of transcription 3 (STAT3) signalling pathway, with GP130 as an intermediate membrane receptor, is involved in the survival, metastasis, and resistance of ovarian cancer. Bazedoxifene, an FDA‑approved drug, is an inhibitor of GP130 and a selective estrogen modulator (SERM). We studied the mechanism of the combination therapy of bazedoxifene and paclitaxel in inhibiting the IL‑6‑mediated GP130/STAT3 signaling pathway in ovarian cancer. Surface plasmon resonance (SPR) was used to assess the binding of bazedoxifene to GP130. Migration, invasion, and apoptosis of ovarian cancer cells were assessed using bazedoxifene and paclitaxel. In addition, we determined the effects of bazedoxifene and paclitaxel alone or in combination on the GP130/STAT3 pathway and epithelial‑mesenchymal transition (EMT). The results revealed that the combination of bazedoxifene and paclitaxel suppressed cell viability, migration, and invasion in the ovarian cancer cells. In addition, the combination treatment increased apoptosis. Furthermore, bazedoxifene combined with paclitaxel inhibited the growth of ovarian cancer cells in a xenograft tumour model. This combination reduced STAT3 phosphorylation and suppressed gene expression and EMT. In conclusion, inhibition of GP130/STAT3 signalling and EMT via a combination of bazedoxifene and paclitaxel could be used as a therapeutic strategy by which to overcome ovarian cancer.

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1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2018. CA Cancer J Clin. 68:7–30. 2018. View Article : Google Scholar : PubMed/NCBI
2	Markman M and Mekhail TM: Paclitaxel in cancer therapy. Expert Opin Pharmacother. 3:755–766. 2002. View Article : Google Scholar : PubMed/NCBI
3	Richardson DL, Sill MW, Coleman RL, Sood AK, Pearl ML, Kehoe SM, Carney ME, Hanjani P, Van Le L, Zhou XC, et al: Paclitaxel with and without pazopanib for persistent or recurrent ovarian cancer: A randomized clinical trial. JAMA Oncol. 4:196–202. 2018. View Article : Google Scholar : PubMed/NCBI
4	Pignata S, Lorusso D, Scambia G, Sambataro D, Tamberi S, Cinieri S, Mosconi AM, Orditura M, Brandes AA, Arcangeli V, et al: Pazopanib plus weekly paclitaxel versus weekly paclitaxel alone for platinum-resistant or platinum-refractory advanced ovarian cancer (MITO 11): A randomised, open-label, phase 2 trial. Lancet Oncol. 16:561–568. 2015. View Article : Google Scholar : PubMed/NCBI
5	Browning L, Patel M, Bring Horvath E, Tawara K and Jorcyk C: IL-6 and ovarian cancer: Inflammatory cytokines in promotion of metastasis. Cancer Manag Res. 10:6685–6693. 2018. View Article : Google Scholar : PubMed/NCBI
6	Heo TH, Wahler J and Suh N: Potential therapeutic implications of IL-6/IL-6R/gp130-targeting agents in breast cancer. Oncotarget. 7:154602016. View Article : Google Scholar : PubMed/NCBI
7	Ernst M and Jenkins BJ: Acquiring signalling specificity from the cytokine receptor gp130. Trends Genet. 20:23–32. 2004. View Article : Google Scholar : PubMed/NCBI
8	Rebouissou S, Amessou M, Couchy G, Poussin K, Imbeaud S, Pilati C, Izard T, Balabaud C, Bioulac-Sage P and Zucman-Rossi J: Frequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours. Nature. 457:200–204. 2009. View Article : Google Scholar : PubMed/NCBI
9	Murakami M, Kamimura D and Hirano T: Pleiotropy and specificity: Insights from the interleukin 6 family of cytokines. Immunity. 50:812–831. 2019. View Article : Google Scholar : PubMed/NCBI
10	Ernst M and Putoczki TL: Molecular pathways: IL11 as a tumor-promoting cytokine-translational implications for cancers. Clin Cancer Res. 20:5579–5588. 2014. View Article : Google Scholar : PubMed/NCBI
11	Rose-John S: Interleukin-6 family cytokines. Cold Spring Harb Perspect Biol. 10:a0284152018. View Article : Google Scholar : PubMed/NCBI
12	Bromberg J and Wang TC: Inflammation and cancer: IL-6 and STAT3 complete the link. Cancer Cell. 15:79–80. 2009. View Article : Google Scholar : PubMed/NCBI
13	Haan C, Heinrich PC and Behrmann I: Structural requirements of the interleukin-6 signal transducer gp130 for its interaction with Janus kinase 1: The receptor is crucial for kinase activation. Biochem J. 361:105–111. 2002. View Article : Google Scholar : PubMed/NCBI
14	Taher MY, Davies DM and Maher J: The role of the interleukin (IL)-6/IL-6 receptor axis in cancer. Biochem Soc Trans. 46:1449–1462. 2018. View Article : Google Scholar : PubMed/NCBI
15	Skiniotis G, Boulanger MJ, Garcia KC and Walz T: Signaling conformations of the tall cytokine receptor gp130 when in complex with IL-6 and IL-6 receptor. Nat Struct Mol Biol. 12:545–551. 2005. View Article : Google Scholar : PubMed/NCBI
16	Dijkgraaf EM, Welters MJ, Nortier JW, van der Burg SH and Kroep JR: Interleukin-6/interleukin-6 receptor pathway as a new therapy target in epithelial ovarian cancer. Curr Pharm Des. 18:3816–3827. 2012. View Article : Google Scholar : PubMed/NCBI
17	Levy DE and Darnell JE Jr: Stats: Transcriptional control and biological impact. Nat Rev Mol Cell Biol. 3:651–662. 2002. View Article : Google Scholar : PubMed/NCBI
18	Li H, Xiao H, Lin L, Jou D, Kumari V, Lin J and Li C: Drug design targeting protein-protein interactions (PPIs) using multiple ligand simultaneous docking (MLSD) and drug repositioning: Discovery of raloxifene and bazedoxifene as novel inhibitors of IL-6/GP130 interface. J Med Chem. 57:632–641. 2014. View Article : Google Scholar : PubMed/NCBI
19	Fu S, Chen X, Lo HW and Lin J: Combined bazedoxifene and paclitaxel treatments inhibit cell viability, cell migration, colony formation, and tumor growth and induce apoptosis in breast cancer. Cancer Lett. 448:11–19. 2019. View Article : Google Scholar : PubMed/NCBI
20	Kim L, Park S, Park H, Kim H and Heo TH: Bazedoxifene, a GP130 inhibitor, modulates EMT signaling and exhibits antitumor effects in HPV-positive cervical cancer. Int J Mol Sci. 22:86932021. View Article : Google Scholar : PubMed/NCBI
21	Wu X, Cao Y, Xiao H, Li C and Lin J: Bazedoxifene as a novel GP130 inhibitor for pancreatic cancer therapy. Mol Cancer Ther. 15:2609–2619. 2016. View Article : Google Scholar : PubMed/NCBI
22	Tian J, Chen X, Fu S, Zhang R, Pan L, Cao Y, Wu X, Xiao H, Lin HJ, Lo HW, et al: Bazedoxifene is a novel IL-6/GP130 inhibitor for treating triple-negative breast cancer. Breast Cancer Res Treat. 175:553–566. 2019. View Article : Google Scholar : PubMed/NCBI
23	Wei J, Ma L, Lai YH, Zhang R, Li H, Li C and Lin J: Correction to: Bazedoxifene as a novel GP130 inhibitor for colon cancer therapy. J Exp Clin Cancer Res. 38:3742019. View Article : Google Scholar : PubMed/NCBI
24	Hong SS, Choi JH, Lee SY, Park YH, Park KY, Lee JY, Kim J, Gajulapati V, Goo JI, Singh S, et al: A novel small-molecule inhibitor targeting the IL-6 receptor β subunit, glycoprotein 130. J Immunol. 195:237–245. 2015. View Article : Google Scholar : PubMed/NCBI
25	Beaufort CM, Helmijr JC, Piskorz AM, Hoogstraat M, Ruigrok-Ritstier K, Besselink N, Murtaza M, van Ĳcken WF, Heine AA, Smid M, et al: Ovarian cancer cell line panel (OCCP): Clinical importance of in vitro morphological subtypes. PLoS One. 9:e1039882014. View Article : Google Scholar : PubMed/NCBI
26	Fu W, Zhao P, Li H, Fu H, Liu X, Liu Y, Wu J and Fu W: Bazedoxifene enhances paclitaxel efficacy to suppress glioblastoma via altering Hippo/YAP pathway. J Cancer. 11:657–667. 2020. View Article : Google Scholar : PubMed/NCBI
27	Chang Q, Daly L and Bromberg J: The IL-6 feed-forward loop: A driver of tumorigenesis. Semin Immunol. 26:48–53. 2014. View Article : Google Scholar : PubMed/NCBI
28	Huang M, Page C, Reynolds RK and Lin J: Constitutive activation of stat 3 oncogene product in human ovarian carcinoma cells. Gynecol Oncol. 79:67–73. 2000. View Article : Google Scholar : PubMed/NCBI
29	Duan Z, Ames RY, Ryan M, Hornicek FJ, Mankin H and Seiden MV: CDDO-Me, a synthetic triterpenoid, inhibits expression of IL-6 and Stat3 phosphorylation in multi-drug resistant ovarian cancer cells. Cancer Chemother Pharmacol. 63:681–689. 2009. View Article : Google Scholar : PubMed/NCBI
30	Wolf J, Rose-John S and Garbers C: Interleukin-6 and its receptors: A highly regulated and dynamic system. Cytokine. 70:11–20. 2014. View Article : Google Scholar : PubMed/NCBI
31	Xu S, Grande F, Garofalo A and Neamati N: Discovery of a novel orally active small-molecule gp130 inhibitor for the treatment of ovarian cancer. Mol Cancer Ther. 12:937–949. 2013. View Article : Google Scholar : PubMed/NCBI
32	Huang F, Tong X, Fu L and Zhang R: Knockdown of STAT3 by shRNA inhibits the growth of CAOV3 ovarian cancer cell line in vitro and in vivo. Acta Biochim Biophys Sin (Shanghai). 40:519–525. 2008. View Article : Google Scholar : PubMed/NCBI
33	Yu H, Kortylewski M and Pardoll D: Crosstalk between cancer and immune cells: Role of STAT3 in the tumour microenvironment. Nat Rev Immunol. 7:41–51. 2007. View Article : Google Scholar : PubMed/NCBI
34	Hirano T, Ishihara K and Hibi M: Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors. Oncogene. 19:2548–2556. 2000. View Article : Google Scholar : PubMed/NCBI
35	Evan GI and Vousden KH: Proliferation, cell cycle and apoptosis in cancer. Nature. 411:342–348. 2001. View Article : Google Scholar : PubMed/NCBI
36	Ling YH, Yang Y, Tornos C, Singh B and Perez-Soler R: Paclitaxel-induced apoptosis is associated with expression and activation of c-Mos gene product in human ovarian carcinoma SKOV3 cells. Cancer Res. 58:3633–3640. 1998.PubMed/NCBI
37	Orr GA, Verdier-Pinard P, McDaid H and Horwitz SB: Mechanisms of taxol resistance related to microtubules. Oncogene. 22:7280–7295. 2003. View Article : Google Scholar : PubMed/NCBI
38	Jones NA, Turner J, McIlwrath AJ, Brown R and Dive C: Cisplatin-and paclitaxel-induced apoptosis of ovarian carcinoma cells and the relationship between bax and bak up-regulation and the functional status of p53. Mol Pharmacol. 53:819–826. 1998.PubMed/NCBI
39	Nielsen M, Kaestel CG, Eriksen K, Woetmann A, Stokkedal T, Kaltoft K, Geisler C, Röpke C and Odum N: Inhibition of constitutively activated Stat3 correlates with altered Bcl-2/Bax expression and induction of apoptosis in mycosis fungoides tumor cells. Leukemia. 13:735–738. 1999. View Article : Google Scholar : PubMed/NCBI PubMed/NCBI PubMed/NCBI PubMed/NCBI PubMed/NCBI PubMed/NCBI PubMed/NCBI PubMed/NCBI PubMed/NCBI PubMed/NCBI PubMed/NCBI PubMed/NCBI PubMed/NCBI PubMed/NCBI PubMed/NCBI