Two serine residues of non-metastasis protein 23-H1 are critical in inhibiting signal transducer and activator of transcription 3 activity in human lung cancer cells

Wu,Zhihao; Guo,Lili; Ge,Jiangnan; Zhang,Zhijian; Wei,Huijun; Zhou,Qinghua

doi:10.3892/ol.2017.6363

Two serine residues of non-metastasis protein 23-H1 are critical in inhibiting signal transducer and activator of transcription 3 activity in human lung cancer cells

Authors:
- Zhihao Wu
- Lili Guo
- Jiangnan Ge
- Zhijian Zhang
- Huijun Wei
- Qinghua Zhou
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Affiliations: Department of Medical Biology, Wannan Medical College, Wuhu, Anhui 241002, P.R. China, Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Center and Institute, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China, Department of Central Laboratory, Wannan Medical College, Wuhu, Anhui 241002, P.R. China
Published online on: June 9, 2017 https://doi.org/10.3892/ol.2017.6363
Pages: 2475-2482

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Abstract

Constitutive activation of signal transducer and activator of transcription 3 (STAT3) in numerous cancers, including lung cancer, is one of the major mechanisms of tumor progression and metastasis. The authors previously reported that the metastasis suppressor non‑metastasis protein 23‑H1 (Nm23‑H1) negatively regulates STAT3 activity by inhibiting its phosphorylation on Tyr705. Nm23‑H1 is a multifunction protein that has three different kinase activities. By transfecting the five mutants that inactivated three different kinase activities respectively into Nm23‑H1 deficient lung cancer cell lines, it was identified that Nm23‑H1S44A (Ser44 to Ala) and Nm23‑H1S120G (Ser120 to Gly) mutant forms were unable to suppress STAT3 phosphorylation on Tyr705, resulting in increased expression of fibronectin and matrix metalloproteinase-9. Notably, protein inhibitor of activated STAT3 was also involved in Nm23‑H1S44A‑ and Nm23‑H1S120G‑mediated suppression of STAT3 phosphorylation. The present results indicated that Ser44 and Ser120 sites of Nm23‑H1 may be responsible for its biological suppressive effects of STAT3 and tumor metastasis, which may contribute to illuminate the metastasis suppression function of Nm23‑H1 in lung cancer.

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1	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
2	Johnston PA and Grandis JR: STAT3 signaling: Anticancer strategies and challenges. Mol Interv. 11:18–26. 2011. View Article : Google Scholar : PubMed/NCBI
3	Song Y, Qian L, Song S, Chen L, Zhang Y, Yuan G, Zhang H, Xia Q, Hu M, Yu M, et al: Fra-1 and Stat3 synergistically regulate activation of human MMP-9 gene. Mol Immunol. 45:137–143. 2008. View Article : Google Scholar : PubMed/NCBI
4	Xie TX, Wei D, Liu M, Gao AC, Ali-Osman F, Sawaya R and Huang S: Stat3 activation regulates the expression of matrix metalloproteinase-2 and tumor invasion and metastasis. Oncogene. 23:3550–3560. 2004. View Article : Google Scholar : PubMed/NCBI
5	Cheng GZ, Zhang WZ, Sun M, Wang Q, Coppola D, Mansour M, Xu LM, Costanzo C, Cheng JQ and Wang LH: Twist is transcriptionally induced by activation of STAT3 and mediates STAT3 oncogenic function. J Biol Chem. 283:14665–14673. 2008. View Article : Google Scholar : PubMed/NCBI
6	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
7	Wei D, Le X, Zheng L, Wang L, Frey JA, Gao AC, Peng Z, Huang S, Xiong HQ, Abbruzzese JL and Xie K: Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. Oncogene. 22:319–329. 2003. View Article : Google Scholar : PubMed/NCBI
8	Xu Q, Briggs J, Park S, Niu G, Kortylewski M, Zhang S, Gritsko T, Turkson J, Kay H, Semenza GL, et al: Targeting Stat3 blocks both HIF-1 and VEGF expression induced by multiple oncogenic growth signaling pathways. Oncogene. 24:5552–5560. 2005. View Article : Google Scholar : PubMed/NCBI
9	Yahata Y, Shirakata Y, Tokumaru S, Yamasaki K, Sayama K, Hanakawa Y, Detmar M and Hashimoto K: Nuclear translocation of phosphorylated STAT3 is essential for vascular endothelial growth factor-induced human dermal microvascular endothelial cell migration and tube formation. J Biol Chem. 278:40026–40031. 2003. View Article : Google Scholar : PubMed/NCBI
10	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
11	Yu XT, Zhu SN, Xu ZD, Hu XQ, Zhu TF, Chen JQ and Lu SL: Roles of EGFR-Stat3 signal pathway in carcinogenesis of experimental hepatoma in rats. J Cancer Res Clin Oncol. 133:145–152. 2007. View Article : Google Scholar : PubMed/NCBI
12	Shuai K: Regulation of cytokine signaling pathways by PIAS proteins. Cell Res. 16:196–202. 2006. View Article : Google Scholar : PubMed/NCBI
13	Croker BA, Kiu H and Nicholson SE: SOCS regulation of the JAK/STAT signalling pathway. Semin Cell Dev Biol. 19:414–422. 2008. View Article : Google Scholar : PubMed/NCBI
14	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
15	Gong L, Wu Z, Guo L, Li L, Zhao R, Zhu D and Zhou Q: Metastasis suppressor Nm23-H1 inhibits STAT3 signaling via a negative feedback mechanism. Biochem Biophys Res Commun. 434:541–546. 2013. View Article : Google Scholar : PubMed/NCBI
16	Steeg PS, Bevilacqua G, Pozzatti R, Liotta LA and Sobel ME: Altered expression of NM23, a gene associated with low tumor metastatic potential, during adenovirus 2 Ela inhibition of experimental metastasis. Cancer Res. 48:6550–6554. 1988.PubMed/NCBI
17	Hartsough MT and Steeg PS: Nm23/nucleoside diphosphate kinase in human cancers. J Bioenerg Biomembr. 32:301–308. 2000. View Article : Google Scholar : PubMed/NCBI
18	Steeg PS, Palmieri D, Ouatas T and Salerno M: Histidine kinases and histidine phosphorylated proteins in mammalian cell biology, signal transduction and cancer. Cancer Lett. 190:1–12. 2003. View Article : Google Scholar : PubMed/NCBI
19	Lu Z, Guo L, Li L, Wu Z and Zhou Q: Construction and expression of nm23-H1 gene with different enzyme activities and resistant specific shRNA in eukaryotic expression vector. Zhongguo Fei Ai Za Zhi. 17:183–188. 2014.(In Chinese). PubMed/NCBI
20	Guo L, Li L, Wang W, Pan Z, Zhou Q and Wu Z: Mitochondrial reactive oxygen species mediates nicotine-induced hypoxia-inducible factor-1α expression in human non-small cell lung cancer cells. Biochim Biophys Acta. 1822:852–861. 2012. View Article : Google Scholar : PubMed/NCBI
21	Xie TX, Huang FJ, Aldape KD, Kang SH, Liu M, Gershenwald JE, Xie K, Sawaya R and Huang S: Activation of Stat3 in human melanoma promotes brain metastasis. Cancer Res. 66:3188–3196. 2006. View Article : Google Scholar : PubMed/NCBI
22	MacDonald NJ, De la Rosa A, Benedict MA, Freije JM, Krutsch H and Steeg PS: A serine phosphorylation of Nm23, and not its nucleoside diphosphate kinase activity, correlates with suppression of tumor metastatic potential. J Biol Chem. 268:25780–25789. 1993.PubMed/NCBI
23	Otsuki Y, Tanaka M, Yoshii S, Kawazoe N, Nakaya K and Sugimura H: Tumor metastasis suppressor nm23H1 regulates Rac1 GTPase by interaction with Tiam1. Proc Natl Acad Sci USA. 98:pp. 4385–4390. 2001; View Article : Google Scholar : PubMed/NCBI
24	Auzenne EJ, Klostergaard J, Mandal PK, Liao WS, Lu Z, Gao F, Bast RC Jr, Robertson FM and McMurray JS: A phosphopeptide mimetic prodrug targeting the SH2 domain of STAT3 inhibits tumor growth and angiogenesis. J Exp Ther Oncol. 10:155–162. 2012.PubMed/NCBI
25	Mandal PK, Gao F, Lu Z, Ren Z, Ramesh R, Birtwistle JS, Kaluarachchi KK, Chen X, Bast RC Jr, Liao WS and McMurray JS: Potent and selective phosphopeptide mimetic prodrugs targeted to the Src homology 2 (SH2) domain of signal transducer and activator of transcription 3. J Med Chem. 54:3549–5463. 2011. View Article : Google Scholar : PubMed/NCBI
26	Siveen KS, Sikka S, Surana R, Dai X, Zhang J, Kumar AP, Tan BK, Sethi G and Bishayee A: Targeting the STAT3 signaling pathway in cancer: Role of synthetic and natural inhibitors. Biochim Biophys Acta. 1845:136–154. 2014.PubMed/NCBI
27	Dabir S, Kluge A, McColl K, Liu Y, Lam M, Halmos B, Wildey G and Dowlati A: PIAS3 activates the intrinsic apoptotic pathway in non-small cell lung cancer cells independent of p53 status. Int J Cancer. 134:1045–1054. 2014. View Article : Google Scholar : PubMed/NCBI
28	Abbas R, McColl KS, Kresak A, Yang M, Chen Y, Fu P, Wildey G and Dowlati A: PIAS3 expression in squamous cell lung cancer is low and predicts overall survival. Cancer Med. 4:325–332. 2015. View Article : Google Scholar : PubMed/NCBI