, Volume 68, Issue 3, pp 389–397 | Cite as

Oridonin suppress cell migration via regulation of nonmuscle myosin IIA

Original Research


Oridonin, which is isolated from Chinese herb Rabdosia rubescens (Hemsl.) Hara, has been implicated in regulation of tumor cell migration and invasion. In this study, treatment with oridonin enhanced the phosphorylation of myosin regulatory light chain (T18/S19) that regulates the ATPase activity of myosin IIA. Meanwhile, stress fibers were significantly more prominent after oridonin incubation, which impaired cell migration in transwell migration assays. All of these effects may be caused by the decreased interaction between myosin IIA and myosin phosphatase complex, but not kinases. Our data provide clear evidence of this novel pharmacological function for oridonin in treating cancer cell migration.


Oridonin Migration Myosin IIA Regulatory light chain Phosphatase complex 



Myosin light chain kinase


Myosin phosphatase-targeting subunit 1


Nonmuscle myosin II


Nonmuscle myosin heavy chain


Catalytic subunit of protein phosphatase type 1δ


Regulatory light chain


Rho-associated protein kinase



This work was supported by the National Natural Science Foundation of China (NSFC No. 81172961).

Conflict of interest

The authors declare that there are no conflicts of interest.


  1. Betapudi V, Licate LS, Egelhoff TT (2006) Distinct roles of nonmuscle myosin II isoforms in the regulation of MDA-MB-231 breast cancer cell spreading and migration. Cancer Res 66:4725–4733CrossRefGoogle Scholar
  2. Cai Y, Biais N, Giannone G, Tanase M, Jiang G, Hofman JM, Wiggins CH, Silberzan P, Buguin A, Ladoux B et al (2006) Nonmuscle myosin IIA-dependent force inhibits cell spreading and drives F-actin flow. Biophys J 91:3907–3920CrossRefGoogle Scholar
  3. Choi CK, Vicente-Manzanares M, Zareno J, Whitmore LA, Mogilner A, Horwitz AR (2008) Actin and alpha-actinin orchestrate the assembly and maturation of nascent adhesions in a myosin II motor-independent manner. Nat Cell Biol 10:1039–1050CrossRefGoogle Scholar
  4. Even-Ram S, Doyle AD, Conti MA, Matsumoto K, Adelstein RS, Yamada KM (2007) Myosin IIA regulates cell motility and actomyosin-microtubule crosstalk. Nat Cell Biol 9:299–309CrossRefGoogle Scholar
  5. Feng J, Ito M, Ichikawa K, Isaka N, Nishikawa M, Hartshorne DJ, Nakano T (1999) Inhibitory phosphorylation site for Rho-associated kinase on smooth muscle myosin phosphatase. J Biol Chem 274:37385–37390CrossRefGoogle Scholar
  6. Friedl P, Wolf K (2003) Tumour-cell invasion and migration: diversity and escape mechanisms. Nat Rev Cancer 3:362–374CrossRefGoogle Scholar
  7. Fujita E, Nagao Y, Kaneko K, Nakazawa S, Kuroda H (1976) The antitumor and antibacterial activity of the Isodon diterpenoids. Chem Pharm Bull (Tokyo) 24:2118–2127CrossRefGoogle Scholar
  8. Gai RY, Xu HL, Qu XJ, Wang FS, Lou HX, Han JX, Nakata M, Kokudo N, Sugawara Y, Kuroiwa C, Tang W (2008) Dynamic of modernizing traditional Chinese medicine and the standards system for its development. Drug Discov Ther 2:2–4Google Scholar
  9. Hartshorne DJ, Ito M, Erdodi F (2004) Role of protein phosphatase type 1 in contractile functions: myosin phosphatase. J Biol Chem 279:37211–37214CrossRefGoogle Scholar
  10. Heath JP, Holifield BF (1991) Cell locomotion: new research tests old ideas on membrane and cytoskeletal flow. Cell Motil Cytoskeleton 18:245–257CrossRefGoogle Scholar
  11. Hirata N, Takahashi M, Yazawa M (2009) Diphosphorylation of regulatory light chain of myosin IIA is responsible for proper cell spreading. Biochem Biophys Res Commun 381:682–687CrossRefGoogle Scholar
  12. Hsieh TC, Wijeratne EK, Liang JY, Gunatilaka AL, Wu JM (2005) Differential control of growth, cell cycle progression, and expression of NF-kappaB in human breast cancer cells MCF-7, MCF-10A, and MDA-MB-231 by ponicidin and oridonin, diterpenoids from the chinese herb Rabdosia rubescens. Biochem Biophys Res Commun 337:224–231CrossRefGoogle Scholar
  13. Huang J, Wu L, Tashiro S, Onodera S, Ikejima T (2008) Reactive oxygen species mediate oridonin-induced HepG2 apoptosis through p53, MAPK, and mitochondrial signaling pathways. J Pharmacol Sci 107:370–379CrossRefGoogle Scholar
  14. Huang Y, Arora P, McCulloch CA, Vogel WF (2009) The collagen receptor DDR1 regulates cell spreading and motility by associating with myosin IIA. J Cell Sci 122:1637–1646CrossRefGoogle Scholar
  15. Kang N, Zhang JH, Qiu F, Tashiro S, Onodera S, Ikejima T (2010) Inhibition of EGFR signaling augments oridonin-induced apoptosis in human laryngeal cancer cells via enhancing oxidative stress coincident with activation of both the intrinsic and extrinsic apoptotic pathways. Cancer Lett 294:147–158CrossRefGoogle Scholar
  16. Kimura K, Ito M, Amano M, Chihara K, Fukata Y, Nakafuku M, Yamamori B, Feng J, Nakano T, Okawa K, Iwamatsu A, Kaibuchi K (1996) Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Science 273:245–248CrossRefGoogle Scholar
  17. Le K, Li CC, Ye G, Moss J, Vaughan M (2013) Arf guanine nucleotide-exchange factors BIG1 and BIG2 regulate nonmuscle myosin IIA activity by anchoring myosin phosphatase complex. Proc Natl Acad Sci USA 110:E3162–E3170CrossRefGoogle Scholar
  18. Li CY, Wang EQ, Cheng Y, Bao JK (2011) Oridonin: an active diterpenoid targeting cell cycle arrest, apoptotic and autophagic pathways for cancer therapeutics. Int J Biochem Cell Biol 43:701–704CrossRefGoogle Scholar
  19. Liang S, He L, Zhao X, Miao Y, Gu Y, Guo C, Xue Z, Dou W, Hu F, Wu K, Nie Y, Fan D (2011) MicroRNA let-7f inhibits tumor invasion and metastasis by targeting MYH9 in human gastric cancer. PLoS One 6:e18409CrossRefGoogle Scholar
  20. Matsumura F (2005) Regulation of myosin II during cytokinesis in higher eukaryotes. Trends Cell Biol 15:371–377CrossRefGoogle Scholar
  21. Matsumura F, Hartshorne DJ (2008) Myosin phosphatase target subunit: many roles in cell function. Biochem Biophys Res Commun 369:149–156CrossRefGoogle Scholar
  22. Pollard TD, Borisy GG (2003) Cellular motility driven by assembly and disassembly of actin filaments. Cell 112:453–465CrossRefGoogle Scholar
  23. Ren KK, Wang HZ, Xie LP, Chen DW, Liu X, Sun J, Nie YC, Zhang RQ (2006) The effects of oridonin on cell growth, cell cycle, cell migration and differentiation in melanoma cells. J Ethnopharmacol 103:176–180CrossRefGoogle Scholar
  24. Riento K, Ridley AJ (2003) Rocks: multifunctional kinases in cell behaviour. Nat Rev Mol Cell Biol 4:446–456CrossRefGoogle Scholar
  25. Shirazi A, Iizuka K, Fadden P, Mosse C, Somlyo AP, Somlyo AV, Haystead TA (1994) Purification and characterization of the mammalian myosin light chain phosphatase holoenzyme. The differential effects of the holoenzyme and its subunits on smooth muscle. J Biol Chem 269:31598–31606Google Scholar
  26. Somlyo AP, Somlyo AV (2003) Ca2+ sensitivity of smooth muscle and nonmuscle myosin II: modulated by G proteins, kinases, and myosin phosphatase. Physiol Rev 83:1325–1358CrossRefGoogle Scholar
  27. Tan I, Ng CH, Lim L, Leung T (2001) Phosphorylation of a novel myosin binding subunit of protein phosphatase 1 reveals a conserved mechanism in the regulation of actin cytoskeleton. J Biol Chem 276:21209–21216CrossRefGoogle Scholar
  28. Vicente-Manzanares M, Ma X, Adelstein RS, Horwitz AR (2009) Non-muscle myosin II takes centre stage in cell adhesion and migration. Nat Rev Mol Cell Biol 10:778–790CrossRefGoogle Scholar
  29. Vicente-Manzanares M, Newell-Litwa K, Bachir AI, Whitmore LA, Horwitz AR (2011) Myosin IIA/IIB restrict adhesive and protrusive signaling to generate front–back polarity in migrating cells. J Cell Biol 193:381–396CrossRefGoogle Scholar
  30. Wang A, Ma X, Conti MA, Adelstein RS (2011) Distinct and redundant roles of the non-muscle myosin II isoforms and functional domains. Biochem Soc Trans 39:1131–1135CrossRefGoogle Scholar
  31. Wang S, Zhong Z, Wan J, Tan W, Wu G, Chen M, Wang Y (2013) Oridonin induces apoptosis, inhibits migration and invasion on highly-metastatic human breast cancer cells. Am J Chin Med 41:177–196CrossRefGoogle Scholar
  32. Wong R, Sagar CM, Sagar SM (2001) Integration of Chinese medicine into supportive cancer care: a modern role for an ancient tradition. Cancer Treat Rev 27:235–246CrossRefGoogle Scholar
  33. Wong CC, Wong CM, Ko FC, Chan LK, Ching YP, Yam JW, Ng IO (2008) Deleted in liver cancer 1 (DLC1) negatively regulates Rho/ROCK/MLC pathway in hepatocellular carcinoma. PLoS One 3:e2779CrossRefGoogle Scholar
  34. Zhou GB, Chen SJ, Wang ZY, Chen Z (2007) Back to the future of oridonin: again, compound from medicinal herb shows potent antileukemia efficacies in vitro and in vivo. Cell Res 17:274–276CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  1. 1.School of Pharmaceutical SciencesZhengzhou UniversityZhengzhouPeople’s Republic of China

Personalised recommendations