Minecoside promotes apoptotic progression through STAT3 inactivation in breast cancer cells

Kim,Buyun; Lee,Ki Yong; Park,Byoungduck

doi:10.3892/ol.2022.13214

Minecoside promotes apoptotic progression through STAT3 inactivation in breast cancer cells

Authors:
- Buyun Kim
- Ki Yong Lee
- Byoungduck Park
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Affiliations: College of Pharmacy, Keimyung University, Dalseo‑Gu, Daegu, North Gyeongsang 704‑701, Republic of Korea, College of Pharmacy, Korea University, Sejong 339‑770, Republic of Korea
Published online on: January 27, 2022 https://doi.org/10.3892/ol.2022.13214
Article Number: 94
Copyright: © Kim et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Breast cancer is one of the most common malignant tumors in women worldwide, and is a major cause of mortality and morbidity in cancer patients. Constitutive activation of STAT3 has been found in a variety of malignant tumors, including breast cancer. Since STAT3 activation is capable of regulating various important features of tumor cells, identification of a novel STAT3 inhibitor is considered a potential strategy for treating breast cancer. The aim of the present study was to examine whether minecoside (MIN), an active compound extracted from Veronica peregrina L., exerts an antitumor effect by inhibiting STAT3 signaling pathway in MDA‑MB‑231 cells. The results revealed that MIN inhibited the constitutive STAT3 activation in a dose‑ and time‑dependent manner. MIN also blocked the nuclear translocation of STAT3 and suppressed STAT3‑DNA binding. In addition, MIN downregulated the STAT3‑mediated expression of proteins such as Bcl‑xL, Bcl‑2, CXCR4, VEGF, and cyclin D1. Subsequently, MIN promoted the caspase‑dependent apoptosis in MDA‑MB‑231 cells. Overall, results of the present study provide evidence that MIN exerted anticancer activity via inhibition of the STAT3 signaling pathway. Further studies using animal models are required to determine the potential of this molecule as an anticancer drug.

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1	DeSantis C, Siegel R, Bandi P and Jemal A: Breast cancer statistics, 2011. CA Cancer J Clin. 61:409–418. 2011. View Article : Google Scholar : PubMed/NCBI
2	Foulkes WD, Smith IE and Reis-Filho JS: Triple-negative breast cancer. N Engl J Med. 363:1938–1948. 2010. View Article : Google Scholar : PubMed/NCBI
3	Dean M, Fojo T and Bates S: Tumour stem cells and drug resistance. Nat Rev Cancer. 5:275–284. 2005. View Article : Google Scholar : PubMed/NCBI
4	Banerjee K and Resat H: Constitutive activation of STAT3 in breast cancer cells: A review. Int J Cancer. 138:2570–2578. 2016. View Article : Google Scholar : PubMed/NCBI
5	Laudisi F, Cherubini F, Monteleone G and Stolfi C: STAT3 interactors as potential therapeutic targets for cancer treatment. Int J Mol Sci. 19:17872018. View Article : Google Scholar : PubMed/NCBI
6	Garbers C, Aparicio-Siegmund S and Rose-John S: The IL-6/gp130/STAT3 signaling axis: Recent advances towards specific inhibition. Curr Opin Immunol. 34:75–82. 2015. View Article : Google Scholar : PubMed/NCBI
7	Becker C, Fantini MC, Schramm C, Lehr HA, Wirtz S, Nikolaev A, Burg J, Strand S, Kiesslich R, Huber S, et al: TGF-beta suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling. Immunity. 21:491–501. 2004. View Article : Google Scholar : PubMed/NCBI
8	Kundu J, Choi BY, Jeong CH, Kundu JK and Chun KS: Thymoquinone induces apoptosis in human colon cancer HCT116 cells through inactivation of STAT3 by blocking JAK2- and Src-mediated phosphorylation of EGF receptor tyrosine kinase. Oncol Rep. 32:821–828. 2014. View Article : Google Scholar : PubMed/NCBI
9	Wang X, Crowe PJ, Goldstein D and Yang JL: STAT3 inhibition, a novel approach to enhancing targeted therapy in human cancers (Review). Int J Oncol. 41:1181–1191. 2012. View Article : Google Scholar : PubMed/NCBI
10	Gu F, Dubé N, Kim JW, Cheng A, Ibarra-Sanchez Mde J, Tremblay ML and Boisclair YR: Protein tyrosine phosphatase 1B attenuates growth hormone-mediated JAK2-STAT signaling. Mol Cell Biol. 23:3753–3762. 2003. View Article : Google Scholar : PubMed/NCBI
11	Liu CY, Tseng LM, Su JC, Chang KC, Chu PY, Tai WT, Shiau CW and Chen KF: Novel sorafenib analogues induce apoptosis through SHP-1 dependent STAT3 inactivation in human breast cancer cells. Breast Cancer Res. 15:R632013. View Article : Google Scholar : PubMed/NCBI
12	Wu C, Sun M, Liu L and Zhou GW: The function of the protein tyrosine phosphatase SHP-1 in cancer. Gene. 306:1–12. 2003. View Article : Google Scholar : PubMed/NCBI
13	Joo MK, Park JJ, Yoo HS, Lee BJ, Chun HJ, Lee SW and Bak YT: Epigenetic regulation and anti-tumorigenic effects of SH2-containing protein tyrosine phosphatase 1 (SHP1) in human gastric cancer cells. Tumour Biol. 37:4603–4612. 2016. View Article : Google Scholar : PubMed/NCBI
14	Kwak JH, Kim HJ, Lee KH, Kang SC and Zee OP: Antioxidative iridoid glycosides and phenolic compounds from Veronica peregrina. Arch Pharm Res. 32:207–213. 2009. View Article : Google Scholar : PubMed/NCBI
15	Kim B, Min YH and Park B: Minecoside modulates cell invasion via regulation of CXCR4 expression in breast and colon cancer cells. Planta Med. 86:331–337. 2020. View Article : Google Scholar : PubMed/NCBI
16	Park S, Shin H, Park Y, Choi I, Park B and Lee KY: Characterization of inhibitory constituents of NO production from Catalpa ovata using LC-MS coupled with a cell-based assay. Bioorg Chem. 80:57–63. 2018. View Article : Google Scholar : PubMed/NCBI
17	Kim B, Lee KY and Park B: Crocin suppresses constitutively active STAT3 through induction of protein tyrosine phosphatase SHP-1. J Cell Biochem. 118:3290–3298. 2017. View Article : Google Scholar : PubMed/NCBI
18	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
19	Masciocchi D, Gelain A, Villa S, Meneghetti F and Barlocco D: Signal transducer and activator of transcription 3 (STAT3): A promising target for anticancer therapy. Future Med Chem. 3:567–597. 2011. View Article : Google Scholar : PubMed/NCBI
20	Kim M, Morales LD, Jang IS, Cho YY and Kim DJ: Protein tyrosine phosphatases as potential regulators of STAT3 signaling. Int J Mol Sci. 19:27082018. View Article : Google Scholar : PubMed/NCBI
21	Han Y, Amin HM, Franko B, Frantz C, Shi X and Lai R: Loss of SHP1 enhances JAK3/STAT3 signaling and decreases proteosome degradation of JAK3 and NPM-ALK in ALK⁺ anaplastic large-cell lymphoma. Blood. 108:2796–2803. 2006. View Article : Google Scholar : PubMed/NCBI
22	Jiao H, Berrada K, Yang W, Tabrizi M, Platanias LC and Yi T: Direct association with and dephosphorylation of Jak2 kinase by the SH2-domain-containing protein tyrosine phosphatase SHP-1. Mol Cell Biol. 16:6985–6992. 1996. View Article : Google Scholar : PubMed/NCBI
23	Real PJ, Sierra A, De Juan A, Segovia JC, Lopez-Vega JM and Fernandez-Luna JL: Resistance to chemotherapy via Stat3-dependent overexpression of Bcl-2 in metastatic breast cancer cells. Oncogene. 21:7611–7618. 2002. View Article : Google Scholar : PubMed/NCBI
24	Wang J, Xu J and Xing G: Lycorine inhibits the growth and metastasis of breast cancer through the blockage of STAT3 signaling pathway. Acta Biochim Biophys Sin (Shanghai). 49:771–779. 2017. View Article : Google Scholar : PubMed/NCBI
25	Liu X, Xiao Q, Bai X, Yu Z, Sun M, Zhao H, Mi X, Wang E, Yao W, Jin F, et al: Activation of STAT3 is involved in malignancy mediated by CXCL12-CXCR4 signaling in human breast cancer. Oncol Rep. 32:2760–2768. 2014. View Article : Google Scholar : PubMed/NCBI
26	Niu G, Wright KL, Huang M, Song L, Haura E, Turkson J, Zhang S, Wang T, Sinibaldi D, Coppola D, et al: Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene. 21:2000–2008. 2002. View Article : Google Scholar : PubMed/NCBI
27	Johnston PA and Grandis JR: STAT3 signaling: Anticancer strategies and challenges. Mol Interv. 11:18–26. 2011. View Article : Google Scholar : PubMed/NCBI
28	Burke WM, Jin X, Lin HJ, Huang M, Liu R, Reynolds RK and Lin J: Inhibition of constitutively active Stat3 suppresses growth of human ovarian and breast cancer cells. Oncogene. 20:7925–7934. 2001. View Article : Google Scholar : PubMed/NCBI
29	Wang T, Niu G, Kortylewski M, Burdelya L, Shain K, Zhang S, Bhattacharya R, Gabrilovich D, Heller R, Coppola D, et al: Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med. 10:48–54. 2004. View Article : Google Scholar : PubMed/NCBI
30	Ihle JN: STATs: Signal transducers and activators of transcription. Cell. 84:331–334. 1996. View Article : Google Scholar : PubMed/NCBI
31	Schreiner SJ, Schiavone AP and Smithgall TE: Activation of STAT3 by the Src family kinase Hck requires a functional SH3 domain. J Biol Chem. 277:45680–45687. 2002. View Article : Google Scholar : PubMed/NCBI
32	Huang TT, Su JC, Liu CY, Shiau CW and Chen KF: Alteration of SHP-1/p-STAT3 signaling: A potential target for anticancer therapy. Int J Mol Sci. 18:12342017. View Article : Google Scholar : PubMed/NCBI
33	Santoni M, Massari F, Del Re M, Ciccarese C, Piva F, Principato G, Montironi R, Santini D, Danesi R, Tortora G and Cascinu S: Investigational therapies targeting signal transducer and activator of transcription 3 for the treatment of cancer. Expert Opin Investig Drugs. 24:809–824. 2015. View Article : Google Scholar : PubMed/NCBI
34	Grivennikov SI and Karin M: Dangerous liaisons: STAT3 and NF-kappaB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev. 21:11–19. 2010. View Article : Google Scholar : PubMed/NCBI