DT-13 inhibits cancer cell migration by regulating NMIIA indirectly in the tumor microenvironment

Du,Hongzhi; Huang,Yue; Hou,Xiaoyin; Yu,Xiaowen; Lin,Sensen; Wei,Xiaohui; Li,Ruiming; Khan,Ghulam  Jilany; Yuan,Shengtao; Sun,Li

doi:10.3892/or.2016.4890

DT-13 inhibits cancer cell migration by regulating NMIIA indirectly in the tumor microenvironment

Authors:
- Hongzhi Du
- Yue Huang
- Xiaoyin Hou
- Xiaowen Yu
- Sensen Lin
- Xiaohui Wei
- Ruiming Li
- Ghulam Jilany Khan
- Shengtao Yuan
- Li Sun
View Affiliations

Affiliations: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, Jiangsu 210009, P.R. China, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, Jiangsu 210009, P.R. China, Tasly Research Institute, Tianjin Tasly Holding Group Co., Ltd., Tianjin 300410, P.R. China
Published online on: June 22, 2016 https://doi.org/10.3892/or.2016.4890
Pages: 721-728

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Tumor metastasis is one of the main causes of mortality among patients with malignant tumors. Previous studies concerning tumor metastasis have merely focused on the cancer cells in the tumor. However, an increasing number of studies show that the tumor microenvironment plays a vital role in the progression of cancer, particularly in tumor metastasis. Since fibroblasts and adipocytes are two of the most representative mesenchymal cells in the tumor microenvironment, we established a hypoxia-induced cancer-associated fibroblast (CAF) model and a chemically induced adipocyte model to reveal the effect of the microenvironment on cancer development. In these models, the conditioned medium from the tumor microenvironment was found to significantly promote the migration of human lung cancer cell line 95D and regulate the expression of non-muscle myosin IIA (NMIIA), which is consistent with results in the published literature. Then, we confirmed the hypothesis that the tumor microenvironment can regulate NMIIA in cancer cells and facilitate migration by using the non-muscle myosin II inhibitor, blebbistatin. Thus, this is the first report that the tumor microenvironment can promote cancer cell migration by regulating the expression of NMIIA. Our present data also indicated that DT-13, the saponin monomer 13 of dwarf lilyturf tuber, inhibited cancer cell migration in the tumor microenvironment model. Further results showed that DT-13 exhibited anti-migratory effects by inhibiting the c-raf/ERK1/2 signaling pathway. Consequently, our research confirmed that DT-13 significantly inhibited 95D cell migration in vitro, indicating the potential anti-metastatic effect of DT-13 on lung cancer and the scientific basis for drug development.

View Figures

View References

1	Chen W, Zheng R, Zhang S, Zhao P, Zeng H, Zou X and He J: Annual report on status of cancer in China, 2010. Chin J Cancer Res. 26:48–58. 2014.PubMed/NCBI
2	Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI
3	Leonardi GC, Candido S, Cervello M, Nicolosi D, Raiti F, Travali S, Spandidos DA and Libra M: The tumor microenvironment in hepatocellular carcinoma (Review). Int J Oncol. 40:1733–1747. 2012.PubMed/NCBI
4	Semenza GL: The hypoxic tumor microenvironment: A driving force for breast cancer progression. Biochim Biophys Acta. 1863:382–391. 2016. View Article : Google Scholar
5	De Wever O, Van Bockstal M, Mareel M, Hendrix A and Bracke M: Carcinoma-associated fibroblasts provide operational flexibility in metastasis. Semin Cancer Biol. 25:33–46. 2014. View Article : Google Scholar : PubMed/NCBI
6	Routray S, Sunkavali A and Bari KA: Carcinoma-associated fibroblasts, its implication in head and neck squamous cell carcinoma: A mini review. Oral Dis. 20:246–253. 2014. View Article : Google Scholar
7	Ali AT, Hochfeld WE, Myburgh R and Pepper MS: Adipocyte and adipogenesis. Eur J Cell Biol. 92:229–236. 2013. View Article : Google Scholar : PubMed/NCBI
8	Bochet L, Meulle A, Imbert S, Salles B, Valet P and Muller C: Cancer-associated adipocytes promotes breast tumor radioresistance. Biochem Biophys Res Commun. 411:102–106. 2011. View Article : Google Scholar : PubMed/NCBI
9	Chiu HC, Chang TY, Huang CT, Chao YS and Hsu JT: EGFR and myosin II inhibitors cooperate to suppress EGFR-T790M-mutant NSCLC cells. Mol Oncol. 6:299–310. 2012. View Article : Google Scholar : PubMed/NCBI
10	Gupton SL and Waterman-Storer CM: Spatiotemporal feedback between actomyosin and focal-adhesion systems optimizes rapid cell migration. Cell. 125:1361–1374. 2006. View Article : Google Scholar : PubMed/NCBI
11	Even-Ram S, Doyle AD, Conti MA, Matsumoto K, Adelstein RS and Yamada KM: Myosin IIA regulates cell motility and actomyosin-microtubule crosstalk. Nat Cell Biol. 9:299–309. 2007. View Article : Google Scholar : PubMed/NCBI
12	Hosono Y, Usukura J, Yamaguchi T, Yanagisawa K, Suzuki M and Takahashi T: MYBPH inhibits NM IIA assembly via direct interaction with NMHC IIA and reduces cell motility. Biochem Biophys Res Commun. 428:173–178. 2012. View Article : Google Scholar : PubMed/NCBI
13	Kim JH and Adelstein RS: LPA(1)-induced migration requires nonmuscle myosin II light chain phosphorylation in breast cancer cells. J Cell Physiol. 226:2881–2893. 2011. View Article : Google Scholar : PubMed/NCBI
14	Vicente-Manzanares M, Ma X, Adelstein RS and Horwitz AR: Non-muscle myosin II takes centre stage in cell adhesion and migration. Nat Rev Mol Cell Biol. 10:778–790. 2009. View Article : Google Scholar : PubMed/NCBI
15	Jacobelli J, Friedman RS, Conti MA, Lennon-Dumenil AM, Piel M, Sorensen CM, Adelstein RS and Krummel MF: Confinement-optimized three-dimensional T cell amoeboid motility is modulated via myosin IIA-regulated adhesions. Nat Immunol. 11:953–961. 2010. View Article : Google Scholar : PubMed/NCBI
16	Tanaka C, Ito S, Nishio N, Kodera Y, Sakurai H, Suzuki H, Nakao A and Isobe K: GADD34 suppresses wound healing by upregulating expression of myosin IIA. Transgenic Res. 19:637–645. 2010. View Article : Google Scholar : PubMed/NCBI
17	Betapudi V: Myosin II motor proteins with different functions determine the fate of lamellipodia extension during cell spreading. PLoS One. 5:e85602010. View Article : Google Scholar : PubMed/NCBI
18	Zhang Y, Liu J, Kou J, Yu J and Yu B: DT-13 suppresses MDA-MB-435 cell adhesion and invasion by inhibiting MMP-2/9 via the p38 MAPK pathway. Mol Med Rep. 6:1121–1125. 2012.PubMed/NCBI
19	Zhao R, Sun L, Lin S, Bai X, Yu B, Yuan S and Zhang L: The saponin monomer of dwarf lilyturf tuber, DT-13, inhibits angiogenesis under hypoxia and normoxia via multi-targeting activity. Oncol Rep. 29:1379–1386. 2013.PubMed/NCBI
20	Ren-Ping Z, Sen-Sen L, Yuan ST, Yu BY, Bai XS, Sun L and Zhang LY: DT-13, a saponin of dwarf lilyturf tuber, exhibits anti-cancer activity by down-regulating C-C chemokine receptor type 5 and vascular endothelial growth factor in MDA-MB-435 cells. Chin J Nat Med. 12:24–29. 2014.PubMed/NCBI
21	Lin SS, Fan W, Sun L, Li FF, Zhao RP, Zhang LY, Yu BY and Yuan ST: The saponin DT-13 inhibits gastric cancer cell migration through down-regulation of CCR5-CCL5 axis. Chin J Nat Med. 12:833–840. 2014.PubMed/NCBI
22	Wei X, Lin S, Liu Y, Zhao R, Ghulam JK, Du H, Mao T, Yu B, Yuan S and Sun L: DT-13 attenuates lung cancer metastasis via directly regulating NMIIA activity under hypoxia condition. Oncol Rep. In press.
23	Fang D, Sun L, Lin S, Zhou L, Su N, Yuan S and Yu B: Vinorelbine inhibits angiogenesis and 95D migration via reducing hypoxic fibroblast stromal cell-derived factor 1 secretion. Exp Biol Med (Maywood). 237:1045–1055. 2012. View Article : Google Scholar
24	Zhou L, Sun L, Lin S, Fang D, Zhao R, Zhu J, Liu J, Chen L, Shi W, Yuan S, et al: Inhibition of angiogenic activity of hypoxic fibroblast cell line MRC-5 in vitro by topotecan. Med Oncol. Nov 9–2010.Epub ahead of print.
25	Choi KC, Lee SY, Yoo HJ, Ryu OH, Lee KW, Kim SM, Baik SH and Choi KM: Effect of PPAR-delta agonist on the expression of visfatin, adiponectin, and resistin in rat adipose tissue and 3T3-L1 adipocytes. Biochem Biophys Res Commun. 357:62–67. 2007. View Article : Google Scholar : PubMed/NCBI
26	Gernapudi R, Yao Y, Zhang Y, Wolfson B, Roy S, Duru N, Eades G, Yang P and Zhou Q: Targeting exosomes from preadipocytes inhibits preadipocyte to cancer stem cell signaling in early-stage breast cancer. Breast Cancer Res Treat. 150:685–695. 2015. View Article : Google Scholar : PubMed/NCBI
27	Jean L, Majumdar D, Shi M, Hinkle LE, Diggins NL, Ao M, Broussard JA, Evans JC, Choma DP and Webb DJ: Activation of Rac by Asef2 promotes myosin II-dependent contractility to inhibit cell migration on type I collagen. J Cell Sci. 126:5585–5597. 2013. View Article : Google Scholar : PubMed/NCBI
28	Semov A, Moreno MJ, Onichtchenko A, Abulrob A, Ball M, Ekiel I, Pietrzynski G, Stanimirovic D and Alakhov V: Metastasis-associated protein S100A4 induces angiogenesis through interaction with Annexin II and accelerated plasmin formation. J Biol Chem. 280:20833–20841. 2005. View Article : Google Scholar : PubMed/NCBI
29	Sun Z, Wang S and Zhao RC: The roles of mesenchymal stem cells in tumor inflammatory microenvironment. J Hematol Oncol. 7:142014. View Article : Google Scholar : PubMed/NCBI
30	Du H, Shi H, Chen D, Zhou Y and Che G: Cross-talk between endothelial and tumor cells via basic fibroblast growth factor and vascular endothelial growth factor signaling promotes lung cancer growth and angiogenesis. Oncol Lett. 9:1089–1094. 2015.PubMed/NCBI
31	Derycke L, Stove C, Vercoutter-Edouart AS, De Wever O, Dollé L, Colpaert N, Depypere H, Michalski JC and Bracke M: The role of non-muscle myosin IIA in aggregation and invasion of human MCF-7 breast cancer cells. Int J Dev Biol. 55:835–840. 2011. View Article : Google Scholar : PubMed/NCBI
32	Elliott PR, Irvine AF, Jung HS, Tozawa K, Pastok MW, Picone R, Badyal SK, Basran J, Rudland PS, Barraclough R, et al: Asymmetric mode of Ca²⁺-S100A4 interaction with nonmuscle myosin IIA generates nanomolar affinity required for filament remodeling. Structure. 20:654–666. 2012. View Article : Google Scholar : PubMed/NCBI
33	Bowers RR, Manevich Y, Townsend DM and Tew KD: Sulfiredoxin redox-sensitive interaction with S100A4 and non-muscle myosin IIA regulates cancer cell motility. Biochemistry. 51:7740–7754. 2012. View Article : Google Scholar : PubMed/NCBI
34	Takahashi O, Komaki R, Smith PD, Jürgensmeier JM, Ryan A, Bekele BN, Wistuba II, Jacoby JJ, Korshunova MV, Biernacka A, et al: Combined MEK and VEGFR inhibition in orthotopic human lung cancer models results in enhanced inhibition of tumor angiogenesis, growth, and metastasis. Clin Cancer Res. 18:1641–1654. 2012. View Article : Google Scholar : PubMed/NCBI