Top

Published in:

Open Access 01-12-2018 | Research article

Arsenic trioxide attenuates STAT-3 activity and epithelial-mesenchymal transition through induction of SHP-1 in gastric cancer cells

Authors: Sung Ho Kim, Hyo Soon Yoo, Moon Kyung Joo, Taehyun Kim, Jong-Jae Park, Beom Jae Lee, Hoon Jai Chun, Sang Woo Lee, Young-Tae Bak

Published in: BMC Cancer | Issue 1/2018

Abstract

Background

We investigated the effect of arsenic trioxide (ATO) for inhibition of signal transducer and activator of transcription 3 (STAT3) and epithelial-mesenchymal transition (EMT) in gastric cancer cells, and the role of SH2 domain-containing phosphatase-1 (SHP-1) during this process.

Methods

We used AGS cells, which showed minimal SHP-1 expression and constitutive STAT3 expression. After treatment of ATO, cellular migration and invasion were assessed by using wound closure assay, Matrigel invasion assay and 3-D culture invasion assay. To validate the role of SHP-1, pervanadate, a pharmacologic phosphatase inhibitor, and SHP-1 siRNA were used. Xenograft tumors were produced, and ATO or pervanadate were administered via intraperitoneal (IP) route.

Results

Treatment of ATO 5 and 10 μM significantly decreased cellular migration and invasion in a dose-dependent manner. Western blot showed that ATO upregulated SHP-1 expression and downregulated STAT3 expression, and immunofluorescence showed upregulation with E-cadherin (epithelial marker) and downregulation of Snail1 (mesenchymal marker) expression by ATO treatment. Anti-migration and invasion effect and modulation of SHP-1/STAT3 axis by ATO were attenuated by pervanadate or SHP-1 siRNA. IP injection of ATO significantly decreased the xenograft tumor volume and upregulated SHP-1 expression, which were attenuated by co-IP injection of pervanadate.

Conclusion

Our data suggest that ATO inhibits STAT3 activity and EMT process by upregulation of SHP-1 in gastric cancer cells.

Li Y, Qu X, Qu J, Zhang Y, Liu J, Teng Y, Hu X, Hou K, Liu Y. Arsenic trioxide induces apoptosis and G2/M phase arrest by inducing Cbl to inhibit PI3K/Akt signaling and thereby regulate p53 activation. Cancer Lett. 2009;284(2):208–15.CrossRefPubMed

Gao YH, Zhang HP, Yang SM, Yang Y, Ma YY, Zhang XY, Yang YM. Inactivation of Akt by arsenic trioxide induces cell death via mitochondrial-mediated apoptotic signaling in SGC-7901 human gastric cancer cells. Oncol Rep. 2014;31(4):1645–52.CrossRefPubMed

Jia Y, Liu D, Xiao D, Ma X, Han S, Zheng Y, Sun S, Zhang M, Gao H, Cui X, et al. Expression of AFP and STAT3 is involved in arsenic trioxide-induced apoptosis and inhibition of proliferation in AFP-producing gastric cancer cells. PLoS One. 2013;8(1):e54774.CrossRefPubMedPubMedCentral

Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15(3):178–96.CrossRefPubMedPubMedCentral

Yue P, Turkson J. Targeting STAT3 in cancer: how successful are we? Expert Opin Investig Drugs. 2009;18(1):45–56.CrossRefPubMedPubMedCentral

Lopez-Ruiz P, Rodriguez-Ubreva J, Cariaga AE, Cortes MA, Colas B. SHP-1 in cell-cycle regulation. Anti Cancer Agents Med Chem. 2011;11(1):89–98.CrossRef

Zhang J, Somani AK, Siminovitch KA. Roles of the SHP-1 tyrosine phosphatase in the negative regulation of cell signalling. Semin Immunol. 2000;12(4):361–78.CrossRefPubMed

Joo MK, Park JJ, Yoo HS, Lee BJ, Chun HJ, Lee SW, Bak YT. Epigenetic regulation and anti-tumorigenic effects of SH2-containing protein tyrosine phosphatase 1 (SHP1) in human gastric cancer cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine. 2016;37(4):4603–12.CrossRef

Huang Z, Lee H, Lee E, Kang SK, Nam JM, Lee M. Responsive nematic gels from the self-assembly of aqueous nanofibres. Nat Commun. 2011;2:459.CrossRefPubMed

10.

Liao WT, Jiang D, Yuan J, Cui YM, Shi XW, Chen CM, Bian XW, Deng YJ, Ding YQ. HOXB7 as a prognostic factor and mediator of colorectal cancer progression. Clinical cancer research : an official journal of the American Association for Cancer Research. 2011;17(11):3569–78.CrossRef

11.

Petit V, Massonnet G, Maciorowski Z, Touhami J, Thuleau A, Nemati F, Laval J, Chateau-Joubert S, Servely JL, Vallerand D, et al. Optimization of tumor xenograft dissociation for the profiling of cell surface markers and nutrient transporters. Laboratory investigation; a journal of technical methods and pathology. 2013;93(5):611–21.CrossRefPubMed

12.

Kaufhold S, Bonavida B. Central role of Snail1 in the regulation of EMT and resistance in cancer: a target for therapeutic intervention. Journal of experimental & clinical cancer research : CR. 2014;33:62.CrossRefPubMedCentral

13.

Lee JH, Chiang SY, Nam D, Chung WS, Lee J, Na YS, Sethi G, Ahn KS. Capillarisin inhibits constitutive and inducible STAT3 activation through induction of SHP-1 and SHP-2 tyrosine phosphatases. Cancer Lett. 2014;345(1):140–8.CrossRefPubMed

14.

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(2):282–92.PubMedPubMedCentral

15.

Jackson CB, Giraud AS. STAT3 as a prognostic marker in human gastric cancer. J Gastroenterol Hepatol. 2009;24(4):505–7.CrossRefPubMed

16.

Joo MK, Park JJ, Kim SH, Yoo HS, Lee BJ, Chun HJ, Lee SW, Bak YT. Antitumorigenic effect of plumbagin by induction of SH2-containing protein tyrosine phosphatase 1 in human gastric cancer cells. Int J Oncol. 2015;46(6):2380–8.CrossRefPubMed

17.

Ji K, Zhang L, Zhang M, Chu Q, Li X, Wang W. Prognostic value and Clinicopathological significance of p-stat3 among gastric carcinoma patients: a systematic review and meta-analysis. Medicine. 2016;95(5):e2641.CrossRefPubMedPubMedCentral

18.

Han JC, Zhang KL, Chen XY, Jiang HF, Kong QY, Sun Y, Wu ML, Huang L, Li H, Liu J. Expression of seven gastric cancer-associated genes and its relevance for Wnt, NF-kappaB and Stat3 signaling. APMIS : acta pathologica, microbiologica, et immunologica Scandinavica. 2007;115(12):1331–43.CrossRefPubMed

19.

Giraud AS, Menheniott TR, Judd LM. Targeting STAT3 in gastric cancer. Expert Opin Ther Targets. 2012;16(9):889–901.CrossRefPubMed

20.

Iida T, Iwahashi M, Katsuda M, Ishida K, Nakamori M, Nakamura M, Naka T, Ojima T, Ueda K, Hayata K, et al. Tumor-infiltrating CD4+ Th17 cells produce IL-17 in tumor microenvironment and promote tumor progression in human gastric cancer. Oncol Rep. 2011;25(5):1271–7.PubMed

21.

Liu X, Jin H, Zhang G, Lin X, Chen C, Sun J, Zhang Y, Zhang Q, Yu J. Intratumor IL-17-positive mast cells are the major source of the IL-17 that is predictive of survival in gastric cancer patients. PLoS One. 2014;9(9):e106834.CrossRefPubMedPubMedCentral

22.

Stuart E, Buchert M, Putoczki T, Thiem S, Farid R, Elzer J, Huszar D, Waring PM, Phesse TJ, Ernst M. Therapeutic inhibition of Jak activity inhibits progression of gastrointestinal tumors in mice. Mol Cancer Ther. 2014;13(2):468–74.CrossRefPubMed

23.

Judd LM, Menheniott TR, Ling H, Jackson CB, Howlett M, Kalantzis A, Priebe W, Giraud AS. Inhibition of the JAK2/STAT3 pathway reduces gastric cancer growth in vitro and in vivo. PLoS One. 2014;9(5):e95993.CrossRefPubMedPubMedCentral

24.

Buchert M, Burns CJ, Ernst M. Targeting JAK kinase in solid tumors: emerging opportunities and challenges. Oncogene. 2016;35(8):939–51.CrossRefPubMed

25.

Oh DY, Lee SH, Han SW, Kim MJ, Kim TM, Kim TY, Heo DS, Yuasa M, Yanagihara Y, Bang YJ. Phase I study of OPB-31121, an oral STAT3 inhibitor, in patients with advanced solid tumors. Cancer research and treatment : official journal of Korean Cancer Association. 2015;47(4):607–15.CrossRef

26.

Fan LC, Shiau CW, Tai WT, Hung MH, Chu PY, Hsieh FS, Lin H, Yu HC, Chen KF. SHP-1 is a negative regulator of epithelial-mesenchymal transition in hepatocellular carcinoma. Oncogene. 2015;34(41):5252–63.CrossRefPubMed

27.

Sun T, Du W, Xiong H, Yu Y, Weng Y, Ren L, Zhao H, Wang Y, Chen Y, Xu J, et al. TMEFF2 deregulation contributes to gastric carcinogenesis and indicates poor survival outcome. Clinical cancer research : an official journal of the American Association for Cancer Research. 2014;20(17):4689–704.CrossRef

28.

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. Clinical cancer research : an official journal of the American Association for Cancer Research. 2010;16(21):5189–99.CrossRef

29.

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(2):452–63.CrossRefPubMed

30.

Tai WT, Chu PY, Shiau CW, Chen YL, Li YS, Hung MH, Chen LJ, Chen PL, Su JC, Lin PY, et al. STAT3 mediates regorafenib-induced apoptosis in hepatocellular carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research. 2014;20(22):5768–76.CrossRef

31.

Tai WT, Shiau CW, Chen PJ, Chu PY, Huang HP, Liu CY, Huang JW, Chen KF. Discovery of novel Src homology region 2 domain-containing phosphatase 1 agonists from sorafenib for the treatment of hepatocellular carcinoma. Hepatology. 2014;59(1):190–201.CrossRefPubMed

32.

Liu SH, Wang KB, Lan KH, Lee WJ, Pan HC, Wu SM, Peng YC, Chen YC, Shen CC, Cheng HC, et al. Calpain/SHP-1 interaction by honokiol dampening peritoneal dissemination of gastric cancer in nu/nu mice. PLoS One. 2012;7(8):e43711.CrossRefPubMedPubMedCentral

33.

Zhao YY, Yu L, Liu BL, He XJ, Zhang BY. Downregulation of P-gp, Ras and p-ERK1/2 contributes to the arsenic trioxide-induced reduction in drug resistance towards doxorubicin in gastric cancer cell lines. Mol Med Rep. 2015;12(5):7335–43.CrossRefPubMedPubMedCentral

34.

Huang S, Chen M, Ding X, Zhang X, Zou X. Proton pump inhibitor selectively suppresses proliferation and restores the chemosensitivity of gastric cancer cells by inhibiting STAT3 signaling pathway. Int Immunopharmacol. 2013;17(3):585–92.CrossRefPubMed

Title: Arsenic trioxide attenuates STAT-3 activity and epithelial-mesenchymal transition through induction of SHP-1 in gastric cancer cells
Authors: Sung Ho Kim
Hyo Soon Yoo
Moon Kyung Joo
Taehyun Kim
Jong-Jae Park
Beom Jae Lee
Hoon Jai Chun
Sang Woo Lee
Young-Tae Bak
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: BMC Cancer / Issue 1/2018
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-018-4071-9

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2018

ATF-3/miR-590/GOLPH3 signaling pathway regulates proliferation of breast cancer

Risk factors for erlotinib-induced hepatotoxicity: a retrospective follow-up study

The serum-based VeriStrat® test is associated with proinflammatory reactants and clinical outcome in non-small cell lung cancer patients

Early detection of colorectal adenocarcinoma: a clinical decision support tool based on plasma porphyrin accumulation and risk factors

The prognostic impact of decreased pretreatment haemoglobin level on the survival of patients with lung cancer: a systematic review and meta-analysis

Radiomics score: a potential prognostic imaging feature for postoperative survival of solitary HCC patients

Keynote webinar | Spotlight on antibody–drug conjugates in cancer