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Breast Cancer Research
Published in: Breast Cancer Research 4/2013

Open Access 01-08-2013 | Research article

Novel sorafenib analogues induce apoptosis through SHP-1 dependent STAT3 inactivation in human breast cancer cells

Authors: Chun-Yu Liu, Ling-Ming Tseng, Jung-Chen Su, Kung-Chi Chang, Pei-Yi Chu, Wei-Tien Tai, Chung-Wai Shiau, Kuen-Feng Chen

Published in: Breast Cancer Research | Issue 4/2013

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Abstract

Introduction

Signal transducers and activators of transcription 3 (STAT3) signaling is constitutively activated in various cancers including breast cancer and has emerged as a novel potential anti-cancer target. STAT3 has been demonstrated to be a target of sorafenib, and a protein tyrosine phosphatase Src homology 2-domain containing tyrosine phosphatase 1 (SHP-1) has been demonstrated to downregulate p-STAT3 via its phosphatase activity. Here, we tested the efficacy of two sorafenib analogues, SC-1 and SC-43, in breast cancer cells and examined the drug mechanism.

Methods

Breast cancer cell lines were used for in vitro studies. Cell viability was examined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was examined by flow cytometry and western blot. Signal transduction pathways in cells were assessed by western blot. In vivo efficacy of sorafenib, SC-1 and SC-43 was tested in xenografted nude mice.

Results

SC-1 and SC-43 induced more potent apoptosis than sorafenib, in association with downregulation of p-STAT3 and its downstream proteins cyclin D1 and survivin in a dose-dependent manner in breast cancer cell lines (HCC-1937, MDA-MB-468, MDA-MB-231, MDA-MB-453, SK-BR3, MCF-7). Overexpression of STAT3 in MDA-MB-468 cells protected the cells from apoptosis induced by sorafenib, SC-1 and SC-43. Moreover, SC-1 and SC-43 upregulated SHP-1 activity to a greater extent than sorafenib as measured by in vitro phosphatase assays. Knockdown of SHP-1 by siRNA reduced apoptosis induced by SC-1 and SC-43. Importantly, SC-1 and SC-43 showed more efficacious antitumor activity and p-STAT3 downregulation than sorafenib in MDA-MB-468 xenograft tumors.

Conclusions

Novel sorafenib analogues SC-1 and SC-43 induce apoptosis through SHP-1 dependent STAT3 inactivation and demonstrate greater potency than sorafenib in human breast cancer cells.
Literature
1.
Alvarez RH, Valero V, Hortobagyi GN: Emerging targeted therapies for breast cancer. J Clin Oncol 2010, 28:3366–3379.CrossRefPubMed
2.
Howlader N, Noone AM, Krapcho M, Neyman N, Aminou R, Waldron W, Altekruse SF, Kosary CL, Ruhl J, Tatalovich Z, Cho H, Mariotto A, Eisner MP, Lewis DR, Chen HS, Feuer EJ, Cronin KA, Edwards BK: SEER Cancer Statistics Review, 1975–2008. Bethesda, MD: National Cancer Institute; 2011. http://​seer.​cancer.​gov/​csr/​1975_​2008/​, based on November 2010 SEER data submission, posted to the SEER web site
3.
Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, Slamon DJ, Murphy M, Novotny WF, Burchmore M, Shak S, Stewart SJ, Press M: Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 2002, 20:719–726.CrossRefPubMed
4.
Bromberg J: Signal transducers and activators of transcription as regulators of growth, apoptosis and breast development. Breast Cancer Res 2000, 2:86–90.CrossRefPubMedPubMedCentral
5.
Diaz N, Minton S, Cox C, Bowman T, Gritsko T, Garcia R, Eweis I, Wloch M, Livingston S, Seijo E, Cantor A, Lee JH, Beam CA, Sullivan D, Jove R, Muro-Cacho CA: Activation of stat3 in primary tumors from high-risk breast cancer patients is associated with elevated levels of activated SRC and survivin expression. Clin Cancer Res 2006, 12:20–28.CrossRefPubMed
6.
Germain D, Frank DA: Targeting the cytoplasmic and nuclear functions of signal transducers and activators of transcription 3 for cancer therapy. Clin Cancer Res 2007, 13:5665–5669.CrossRefPubMed
7.
Gritsko T, Williams A, Turkson J, Kaneko S, Bowman T, Huang M, Nam S, Eweis I, Diaz N, Sullivan D, Yoder S, Enkemann S, Eschrich S, Lee JH, Beam CA, Cheng J, Minton S, Muro-Cacho CA, Jove R: Persistent activation of stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells. Clin Cancer Res 2006, 12:11–19.CrossRefPubMed
8.
Marotta LL, Almendro V, Marusyk A, Shipitsin M, Schemme J, Walker SR, Bloushtain-Qimron N, Kim JJ, Choudhury SA, Maruyama R, Wu Z, Gönen M, Mulvey LA, Bessarabova MO, Huh SJ, Silver SJ, Kim SY, Park SY, Lee HE, Anderson KS, Richardson AL, Nikolskaya T, Nikolsky Y, Liu XS, Root DE, Hahn WC, Frank DA, Polyak K: The JAK2/STAT3 signaling pathway is required for growth of CD44+CD24- stem cell-like breast cancer cells in human tumors. J Clin Invest 2011, 121:2723–2735.CrossRefPubMedPubMedCentral
9.
Idowu MO, Kmieciak M, Dumur C, Burton RS, Grimes MM, Powers CN, Manjili MH: CD44(+)/CD24(−/low) cancer stem/progenitor cells are more abundant in triple-negative invasive breast carcinoma phenotype and are associated with poor outcome. Hum Pathol 2012, 43:364–373.CrossRefPubMed
10.
Gu F, Dube N, Kim JW, Cheng A, Ibarra-Sanchez Mde J, Tremblay ML, Boisclair YR: Protein tyrosine phosphatase 1B attenuates growth hormone-mediated JAK2-STAT signaling. Mol Cell Biol 2003, 23:3753–3762.CrossRefPubMedPubMedCentral
11.
Kim HY, Park EJ, Joe EH, Jou I: Curcumin suppresses Janus kinase-STAT inflammatory signaling through activation of Src homology 2 domain-containing tyrosine phosphatase 2 in brain microglia. J Immunol 2003, 171:6072–6079.CrossRefPubMed
12.
Tai WT, Cheng AL, Shiau CW, Huang HP, Huang JW, Chen PJ, Chen KF: Signal transducer and activator of transcription 3 is a major kinase-independent target of sorafenib in hepatocellular carcinoma. J Hepatol 2011, 55:1041–1048.CrossRefPubMed
13.
Han Y, Amin HM, Franko B, Frantz C, Shi X, 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 2006, 108:2796–2803.CrossRefPubMed
14.
Witkiewicz A, Raghunath P, Wasik A, Junkins-Hopkins JM, Jones D, Zhang Q, Odum N, Wasik MA: Loss of SHP-1 tyrosine phosphatase expression correlates with the advanced stages of cutaneous T-cell lymphoma. Hum Pathol 2007, 38:462–467.CrossRefPubMed
15.
Pandey MK, Sung B, Aggarwal BB: Betulinic acid suppresses STAT3 activation pathway through induction of protein tyrosine phosphatase SHP-1 in human multiple myeloma cells. Int J Cancer 2010, 127:282–292.PubMedPubMedCentral
16.
Kunnumakkara AB, Nair AS, Sung B, Pandey MK, Aggarwal BB: Boswellic acid blocks signal transducers and activators of transcription 3 signaling, proliferation, and survival of multiple myeloma via the protein tyrosine phosphatase SHP-1. Mol Cancer Res 2009, 7:118–128.CrossRefPubMedPubMedCentral
17.
Prasad S, Pandey MK, Yadav VR, Aggarwal BB: Gambogic acid inhibits STAT3 phosphorylation through activation of protein tyrosine phosphatase SHP-1: potential role in proliferation and apoptosis. Cancer Prev Res (Phila) 2011, 4:1084–1094.CrossRef
18.
Phromnoi K, Prasad S, Gupta SC, Kannappan R, Reuter S, Limtrakul P, Aggarwal BB: Dihydroxypentamethoxyflavone down-regulates constitutive and inducible signal transducers and activators of transcription-3 through the induction of tyrosine phosphatase SHP-1. Mol Pharmacol 2011, 80:889–899.CrossRefPubMedPubMedCentral
19.
Pandey MK, Sung B, Ahn KS, Aggarwal BB: Butein suppresses constitutive and inducible signal transducer and activator of transcription (STAT) 3 activation and STAT3-regulated gene products through the induction of a protein tyrosine phosphatase SHP-1. Mol Pharmacol 2009, 75:525–533.CrossRefPubMed
20.
Kang SH, Jeong SJ, Kim SH, Kim JH, Jung JH, Koh W, Kim DK, Chen CY: Icariside II induces apoptosis in U937 acute myeloid leukemia cells: role of inactivation of STAT3-related signaling. PLoS One 2012, 7:e28706.CrossRefPubMedPubMedCentral
21.
Sandur SK, Pandey MK, Sung B, Aggarwal BB: 5-hydroxy-2-methyl-1,4-naphthoquinone, a vitamin K3 analogue, suppresses STAT3 activation pathway through induction of protein tyrosine phosphatase, SHP-1: potential role in chemosensitization. Mol Cancer Res 2010, 8:107–118.CrossRefPubMedPubMedCentral
22.
Chen KF, Tai WT, Liu TH, Huang HP, Lin YC, Shiau CW, Li PK, Chen PJ, Cheng AL: Sorafenib overcomes TRAIL resistance of hepatocellular carcinoma cells through the inhibition of STAT3. Clin Cancer Res 2010, 16:5189–5199.CrossRefPubMed
23.
Chen KF, Tai WT, Hsu CY, Huang JW, Liu CY, Chen PJ, Kim I, Shiau CW: Blockade of STAT3 activation by sorafenib derivatives through enhancing SHP-1 phosphatase activity. Eur J Med Chem 2012, 55:220–227.CrossRefPubMed
24.
Chen KF, Tai WT, Huang JW, Hsu CY, Chen WL, Cheng AL, Chen PJ, Shiau CW: Sorafenib derivatives induce apoptosis through inhibition of STAT3 independent of Raf. Eur J Med Chem 2011, 46:2845–2851.CrossRefPubMed
25.
Chen KF, Chen HL, Shiau CW, Liu CY, Chu PY, Tai WT, Ichikawa K, Chen PJ, Cheng AL: Sorafenib and its derivative SC-49 sensitize hepatocellular carcinoma cells to CS-1008, a humanized anti-DR5 antibody. Br J Pharmacol 2012, 168:658–672.CrossRef
26.
Wan PT, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM, Jones CM, Marshall CJ, Springer CJ, Barford D, Marais R, Cancer Genome Project: Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 2004, 116:855–867.CrossRefPubMed
27.
Bhattacharya R, Kwon J, Wang E, Mukherjee P, Mukhopadhyay D: Src homology 2 (SH2) domain containing protein tyrosine phosphatase-1 (SHP-1) dephosphorylates VEGF Receptor-2 and attenuates endothelial DNA synthesis, but not migration*. J Mol Signal 2008, 3:8.CrossRefPubMedPubMedCentral
28.
Keilhack H, Tenev T, Nyakatura E, Godovac-Zimmermann J, Nielsen L, Seedorf K, Bohmer FD: Phosphotyrosine 1173 mediates binding of the protein-tyrosine phosphatase SHP-1 to the epidermal growth factor receptor and attenuation of receptor signaling. J Biol Chem 1998, 273:24839–24846.CrossRefPubMed
29.
Yu Z, Su L, Hoglinger O, Jaramillo ML, Banville D, Shen SH: SHP-1 associates with both platelet-derived growth factor receptor and the p85 subunit of phosphatidylinositol 3-kinase. J Biol Chem 1998, 273:3687–3694.CrossRefPubMed
30.
Yip SS, Crew AJ, Gee JM, Hui R, Blamey RW, Robertson JF, Nicholson RI, Sutherland RL, Daly RJ: Up-regulation of the protein tyrosine phosphatase SHP-1 in human breast cancer and correlation with GRB2 expression. Int J Cancer 2000, 88:363–368.CrossRefPubMed
31.
Wu C, Guan Q, Wang Y, Zhao ZJ, Zhou GW: SHP-1 suppresses cancer cell growth by promoting degradation of JAK kinases. J Cell Biochem 2003, 90:1026–1037.CrossRefPubMed
32.
Wu C, Sun M, Liu L, Zhou GW: The function of the protein tyrosine phosphatase SHP-1 in cancer. Gene 2003, 306:1–12.CrossRefPubMed
33.
Thangaraju M, Sharma K, Leber B, Andrews DW, Shen SH, Srikant CB: Regulation of acidification and apoptosis by SHP-1 and Bcl-2. J Biol Chem 1999, 274:29549–29557.CrossRefPubMed
34.
Tassidis H, Culig Z, Wingren AG, Harkonen P: Role of the protein tyrosine phosphatase SHP-1 in interleukin-6 regulation of prostate cancer cells. Prostate 2010, 70:1491–1500.CrossRefPubMed
35.
Lee SH, Lopes De Menezes D, Vora J, Harris A, Ye H, Nordahl L, Garrett E, Samara E, Aukerman SL, Gelb AB, Heise C: In vivo target modulation and biological activity of CHIR-258, a multitargeted growth factor receptor kinase inhibitor, in colon cancer models. Clin Cancer Res 2005, 11:3633–3641.CrossRefPubMed
36.
Chen KF, Chen HL, Liu CY, Tai WT, Ichikawa K, Chen PJ, Cheng AL: Dovitinib sensitizes hepatocellular carcinoma cells to TRAIL and tigatuzumab, a novel anti-DR5 antibody, through SHP-1-dependent inhibition of STAT3. Biochem Pharmacol 2012, 83:769–777.CrossRefPubMed
37.
Tai WT, Cheng AL, Shiau CW, Liu CY, Ko CH, Lin MW, Chen PJ, Chen KF: Dovitinib induces apoptosis and overcomes sorafenib resistance in hepatocellular carcinoma through SHP-1-mediated inhibition of STAT3. Mol Cancer Ther 2012, 11:452–463.CrossRefPubMed
38.
Gradishar WJ: Sorafenib in locally advanced or metastatic breast cancer. Expert Opin Investig Drugs 2012, 21:1177–1191.CrossRefPubMed
39.
40.
Mackey JR, Kerbel RS, Gelmon KA, McLeod DM, Chia SK, Rayson D, Verma S, Collins LL, Paterson AH, Robidoux A, Pritchard KI: Controlling angiogenesis in breast cancer: a systematic review of anti-angiogenic trials. Cancer Treat Rev 2012, 38:673–688.CrossRefPubMed
41.
Insabato L, Amelio I, Quarto M, Zannetti A, Tolino F, de Mauro G, Cerchia L, Riccio P, Baumhoer D, Condorelli G, Terracciano L, de Franciscis V: Elevated expression of the tyrosine phosphatase SHP-1 defines a subset of high-grade breast tumors. Oncology 2009, 77:378–384.CrossRefPubMed
42.
Esposito N, Colavita I, Quintarelli C, Sica AR, Peluso AL, Luciano L, Picardi M, Del Vecchio L, Buonomo T, Hughes TP, White D, Radich JP, Russo D, Branford S, Saglio G, Melo JV, Martinelli R, Ruoppolo M, Kalebic T, Martinelli G, Pane F: SHP-1 expression accounts for resistance to imatinib treatment in Philadelphia chromosome-positive cells derived from patients with chronic myeloid leukemia. Blood 2011, 118:3634–3644.CrossRefPubMed
43.
Wang W, Liu L, Song X, Mo Y, Komma C, Bellamy HD, Zhao ZJ, Zhou GW: Crystal structure of human protein tyrosine phosphatase SHP-1 in the open conformation. J Cell Biochem 2011, 112:2062–2071.CrossRefPubMedPubMedCentral
44.
Yang J, Liu L, He D, Song X, Liang X, Zhao ZJ, Zhou GW: Crystal structure of human protein-tyrosine phosphatase SHP-1. J Biol Chem 2003, 278:6516–6520.CrossRefPubMed
45.
Yang J, Liang X, Niu T, Meng W, Zhao Z, Zhou GW: Crystal structure of the catalytic domain of protein-tyrosine phosphatase SHP-1. J Biol Chem 1998, 273:28199–28207.CrossRefPubMed
46.
Jiao H, Berrada K, Yang W, Tabrizi M, Platanias LC, Yi T: Direct association with and dephosphorylation of Jak2 kinase by the SH2-domain-containing protein tyrosine phosphatase SHP-1. Mol Cell Biol 1996, 16:6985–6992.CrossRefPubMedPubMedCentral
47.
Kozlowski M, Larose L, Lee F, Le DM, Rottapel R, Siminovitch KA: SHP-1 binds and negatively modulates the c-Kit receptor by interaction with tyrosine 569 in the c-Kit juxtamembrane domain. Mol Cell Biol 1998, 18:2089–2099.CrossRefPubMedPubMedCentral
48.
Marsh HN, Dubreuil CI, Quevedo C, Lee A, Majdan M, Walsh GS, Hausdorff S, Said FA, Zoueva O, Kozlowski M, Siminovitch K, Neel BG, Miller FD, Kaplan DR: SHP-1 negatively regulates neuronal survival by functioning as a TrkA phosphatase. J Cell Biol 2003, 163:999–1010.CrossRefPubMedPubMedCentral
Metadata
Title
Novel sorafenib analogues induce apoptosis through SHP-1 dependent STAT3 inactivation in human breast cancer cells
Authors
Chun-Yu Liu
Ling-Ming Tseng
Jung-Chen Su
Kung-Chi Chang
Pei-Yi Chu
Wei-Tien Tai
Chung-Wai Shiau
Kuen-Feng Chen
Publication date
01-08-2013
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 4/2013
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr3457

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