DT-13 attenuates human lung cancer metastasis via regulating NMIIA activity under hypoxia condition

Wei,Xiao-Hui; Lin,Sen-Sen; Liu,Yang; Zhao,Ren-Ping; Khan,Ghulam  Jilany; Du,Hong-Zhi; Mao,Ting-Ting; Yu,Bo-Yang; Li,Rui-Ming; Yuan,Sheng-Tao; Sun,Li

doi:10.3892/or.2016.4879

DT-13 attenuates human lung cancer metastasis via regulating NMIIA activity under hypoxia condition

Authors:
- Xiao-Hui Wei
- Sen-Sen Lin
- Yang Liu
- Ren-Ping Zhao
- Ghulam Jilany Khan
- Hong-Zhi Du
- Ting-Ting Mao
- Bo-Yang Yu
- Rui-Ming Li
- Sheng-Tao Yuan
- Li Sun
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Affiliations: Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, P.R. China, Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, P.R. China, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, P.R. China, Tasly Research Institute, Tianjin Tasly Hodling Group Co., Ltd., Tianjin, P.R. China
Published online on: June 16, 2016 https://doi.org/10.3892/or.2016.4879
Pages: 991-999

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Abstract

Cancer metastasis plays a major role in tumor deterioration. Metastatic processes are known to be regulated by hypoxic microenvironment and non-muscle myosin IIA (NMIIA). DT-13, a bioactive saponin monomer isolated from Ophiopogon japonicus, has been reported to inhibit various cancer metastasis, but whether NMIIA is involved in the anti-metastatic activity of DT-13 under hypoxia remains to be determined. Thus, this study aims to clarify the role of DT-13 in regulating 95D cell metastasis under hypoxic microenvironment and to further investigate whether NMIIA is involved in the anti-metastatic mechanism of DT-13. We found that DT-13 significantly inhibited 95D cells metastasis in vitro and in vivo. Furthermore, hypoxia significantly inhibited the expression of NMIIA and redistributed NMIIA to the cell periphery, whereas DT-13 reversed the hypoxic effects by upregulating the expression of NMIIA. Moreover, DT-13 treatment redistributed NMIIA to the nuclear periphery and reduced the formation of F-actin in 95D cells. In addition, we found that the Raf-ERK1/2 signaling pathway is involved in regulation of NMIIA by DT-13. Collectively, these findings support NMIIA as a target of DT-13 to prevent lung cancer metastasis.

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1	Edwards BK, Noone AM, Mariotto AB, Simard EP, Boscoe FP, Henley SJ, Jemal A, Cho H, Anderson RN, Kohler BA, et al: Annual Report to the Nation on the status of cancer, 1975–2010, featuring prevalence of comorbidity and impact on survival among persons with lung, colorectal, breast, or prostate cancer. Cancer. 120:1290–1314. 2014. View Article : Google Scholar
2	Wang Y and Liu Y, Malek SN, Zheng P and Liu Y: Targeting HIF1α eliminates cancer stem cells in hematological malignancies. Cell Stem Cell. 8:399–411. 2011. View Article : Google Scholar : PubMed/NCBI
3	Luo W, Hu H, Chang R, Zhong J, Knabel M, O'Meally R, Cole RN, Pandey A and Semenza GL: Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell. 145:732–744. 2011. View Article : Google Scholar : PubMed/NCBI
4	Mak P, Leav I, Pursell B, Bae D, Yang X, Taglienti CA, Gouvin LM, Sharma VM and Mercurio AM: ERbeta impedes prostate cancer EMT by destabilizing HIF-1alpha and inhibiting VEGF-mediated snail nuclear localization: Implications for Gleason grading. Cancer Cell. 17:319–332. 2010. View Article : Google Scholar : PubMed/NCBI
5	Swietach P, Vaughan-Jones RD and Harris AL: Regulation of tumor pH and the role of carbonic anhydrase 9. Cancer Metastasis Rev. 26:299–310. 2007. View Article : Google Scholar : PubMed/NCBI
6	Chan DA and Giaccia AJ: Hypoxia, gene expression, and metastasis. Cancer Metastasis Rev. 26:333–339. 2007. View Article : Google Scholar : PubMed/NCBI
7	Semenza GL: Hypoxia-inducible factors in physiology and medicine. Cell. 148:399–408. 2012. View Article : Google Scholar : PubMed/NCBI
8	Zhang H, Wong CCL, Wei H, Gilkes DM, Korangath P, Chaturvedi P, Schito L, Chen J, Krishnamachary B, Winnard PT Jr, et al: HIF-1-dependent expression of angiopoietin-like 4 and L1CAM mediates vascular metastasis of hypoxic breast cancer cells to the lungs. Oncogene. 31:1757–1770. 2012. View Article : Google Scholar
9	Estecha A, Sánchez-Martín L, Puig-Kröger A, Bartolomé RA, Teixidó J, Samaniego R and Sánchez-Mateos P: Moesin orchestrates cortical polarity of melanoma tumour cells to initiate 3D invasion. J Cell Sci. 122:3492–3501. 2009. View Article : Google Scholar : PubMed/NCBI
10	Poincloux R, Collin O, Lizárraga F, Romao M, Debray M, Piel M and Chavrier P: Contractility of the cell rear drives invasion of breast tumor cells in 3D Matrigel. Proc Natl Acad Sci USA. 108:1943–1948. 2011. View Article : Google Scholar : PubMed/NCBI
11	Dahan I, Yearim A, Touboul Y and Ravid S: The tumor suppressor Lgl1 regulates NMII-A cellular distribution and focal adhesion morphology to optimize cell migration. Mol Biol Cell. 23:591–601. 2012. View Article : Google Scholar : PubMed/NCBI
12	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
13	Clark K, Langeslag M, Figdor CG and van Leeuwen FN: Myosin II and mechanotransduction: A balancing act. Trends Cell Biol. 17:178–186. 2007. View Article : Google Scholar : PubMed/NCBI
14	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
15	Doyle AD, Kutys ML, Conti MA, Matsumoto K, Adelstein RS and Yamada KM: Micro-environmental control of cell migration - myosin IIA is required for efficient migration in fibrillar environments through control of cell adhesion dynamics. J Cell Sci. 125:2244–2256. 2012. View Article : Google Scholar : PubMed/NCBI
16	Liu Z, van Grunsven LA, Van Rossen E, Schroyen B, Timmermans JP, Geerts A and Reynaert H: Blebbistatin inhibits contraction and accelerates migration in mouse hepatic stellate cells. Br J Pharmacol. 159:304–315. 2010. View Article : Google Scholar :
17	Liu Z, Van Rossen E, Timmermans JP, Geerts A, van Grunsven LA and Reynaert H: Distinct roles for non-muscle myosin II isoforms in mouse hepatic stellate cells. J Hepatol. 54:132–141. 2011. View Article : Google Scholar
18	Betapudi V, Licate LS and Egelhoff TT: Distinct roles of nonmuscle myosin II isoforms in the regulation of MDA-MB-231 breast cancer cell spreading and migration. Cancer Res. 66:4725–4733. 2006. View Article : Google Scholar : 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 angio-genesis under hypoxia and normoxia via multi-targeting activity. Oncol Rep. 29:1379–1386. 2013.PubMed/NCBI
20	Zhang YY, Liu JH, Kou JP, Yu J and Yu BY: DT-13, a steroidal saponin from Liriope muscari L. H. Bailey, suppresses A549 cells adhesion and invasion by inhibiting MMP-2/9. Chin J Nat Med. 10:436–440. 2012.
21	Yu XW, Lin S, Du HZ, Zhao RP, Feng SY, Yu BY, Zhang LY, Li RM, Qian CM, Luo XJ, et al: Synergistic combination of DT-13 and topotecan inhibits human gastric cancer via myosin IIA-induced endocytosis of egf receptor in vitro and in vivo. Oncotarget. doi: 10.18632. 2016.
22	Schramek D, Sendoel A, Segal JP, Beronja S, Heller E, Oristian D, Reva B and Fuchs E: Direct in vivo RNAi screen unveils myosin IIa as a tumor suppressor of squamous cell carcinomas. Science. 343:309–313. 2014. View Article : Google Scholar : PubMed/NCBI
23	Liu Z, Ho CH and Grinnell F: The different roles of myosin IIA and myosin IIB in contraction of 3D collagen matrices by human fibroblasts. Exp Cell Res. 326:295–306. 2014. View Article : Google Scholar : PubMed/NCBI
24	Casalou C, Seixas C, Portelinha A, Pintado P, Barros M, Ramalho JS, Lopes SS and Barral DC: Arl13b and the non-muscle myosin heavy chain IIA are required for circular dorsal ruffle formation and cell migration. J Cell Sci. 127:2709–2722. 2014. View Article : Google Scholar : PubMed/NCBI
25	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
26	Xia ZK, Yuan YC, Yin N, Yin BL, Tan ZP and Hu YR: Nonmuscle myosin IIA is associated with poor prognosis of esophageal squamous cancer. Dis Esophagus. 25:427–436. 2012. View Article : Google Scholar
27	Jorrisch MH, Shih W and Yamada S: Myosin IIA deficient cells migrate efficiently despite reduced traction forces at cell periphery. Biol Open. 2:368–372. 2013. View Article : Google Scholar : PubMed/NCBI
28	Zhang H, Chen Y, Wadham C, McCaughan GW, Keane FM and Gorrell MD: Dipeptidyl peptidase 9 subcellular localization and a role in cell adhesion involving focal adhesion kinase and paxillin. Biochim Biophys Acta. 1853:470–480. 2015. View Article : Google Scholar
29	Babbin BA, Koch S, Bachar M, Conti MA, Parkos CA, Adelstein RS, Nusrat A and Ivanov AI: Non-muscle myosin IIA differentially regulates intestinal epithelial cell restitution and matrix invasion. Am J Pathol. 174:436–448. 2009. View Article : Google Scholar : PubMed/NCBI