Curcumin Inhibits TGF-β1-Induced MMP-9 and Invasion through ERK and Smad Signaling in Breast Cancer MDA-MB-231 Cells

  • Mo, Na (Department of Pathology, Chongqing Medical University) ;
  • Li, Zheng-Qian (Department of Anesthesiology, Peking University Third Hospital (PUTH)) ;
  • Li, Jing (Department of Pathology, Chongqing Medical University) ;
  • Cao, You-De (Department of Pathology, Chongqing Medical University)
  • Published : 2012.11.30


Objective: To evaluate the effects of curcumin on matrixmetalloproteinase-9 (MMP-9) and invasion ability induced by transforming growth factor-${\beta}1$ (TGF-${\beta}1$) in MDA-MB-231 cells and potential mechanisms. Methods: Human breast cancer MDA-MB-231 cells were used with the CCK-8 assay to measure the cytotoxicity of curcumin. After treatment with 10 ng/ml TGF-${\beta}1$, with or without curcumin (${\leq}10{\mu}M$), cell invasion was checked by transwell chamber. The effects of curcumin on TGF-${\beta}1$-stimulated MMP-9 and phosphorylation of Smad2, extracellular-regulated kinase (ERK), and p38 mitogen activated protein kinases (p38MAPK) were examined by Western blotting. Supernatant liquid were collected to analyze the activity of MMP-9 via zymography. Following treatment with PD98059, a specific inhibitor of ERK, and SB203580, a specific inhibitor of p38MAPK, Western blotting and zymography were employed to examine MMP-9 expression and activity, respectively. Results: Low dose curcumin (${\leq}10{\mu}M$) did not show any obvious toxicity to the cells, while $0{\sim}10{\mu}mol/L$ caused a concentration-dependent reduction in cell invasion provoked by TGF-${\beta}1$. Curcumin also markedly inhibited TGF-${\beta}1$-regulated MMP-9 and activation of Smad2, ERK1/2 and p38 in a dose- and time-dependent manner. Additionally, PD98059, but not SB203580, showed a similar pattern of inhibition of MMP-9 expression. Conclusion: Curcumin inhibited TGF-${\beta}1$-stimulated MMP-9 and the invasive phenotype in MDA-MB-231 cells, possibly associated with TGF-${\beta}$/Smad and TGF-${\beta}$/ERK signaling.


Curcumin;breast cancer;TGF-${\beta}1$;MMP-9;MAPKs;invasion


  1. Allen M, Louise Jones J (2011). Jekyll and Hyde: the role of the microenvironment on the progression of cancer. J Pathol, 223, 162-76.
  2. Bakin AV, Safina A, Rinehart C, et al (2004). A critical role of tropomyosins in TGF-beta regulation of the actin cytoskeleton andcell motility in epithelial cells. Daroqui C, Darbary H, Helfman DM. Mol Biol Cell, 15, 4682-94.
  3. Belotti D, Calcagno C, Garofalo A (2008). Vascular endothelial growth factor stimulates organ-specific host matrix metalloproteinase-9 expression and ovarian cancer invasion. Mol Cancer Res, 6, 525-34.
  4. Biswas S, Guix M, Rinehart C, et al (2007). Inhibition of TGFbeta with neutralizing antibodies prevents radiation-induced acceleration of metastatic cancer progression. J Clin Invest, 117, 1305-13.
  5. Blair KJ, Kiang A, Wang-Rodriguez J, et al (2011). EGF and bFGF promote invasion that is modulated by PI3/Akt kinase and Erk in vestibular schwannoma. Otol Neurotol, 32, 308-14.
  6. Chen P, Lu N, Ling Y, Chen Y, et al (2011). Inhibitory effects of wogonin on the invasion of human breast carcinoma cells by downregulating the expression and activity of matrix me talloproteinase-9. Toxicology, 282, 122-8.
  7. Cheung KL (2007). Endocrine therapy for breast cancer: an overview. Breast, 16, 327-43.
  8. Chou YT, Wang H, Chen Y (2006). Cited2 modulates TGF-betamediated upregulation of MMP9. Oncogene, 25, 5547-60.
  9. Dziembowska M, Danilkiewicz M, Wesolowska A (2007). Cross-talk between Smad and p38 MAPK signalling in transforming growth factor beta signal transduction in human glioblastoma cells. Biochem Biophys Res Commun, 354, 1101-6.
  10. Hassan ZK, Daghestani MH (2012). Curcumin effect on MMPs and TIMPs genes in a breast cancer cell line. Asian Pac J Cancer Prev, 13, 3259-64.
  11. Hortobagyi GN (2002). The status of breast cancer management: challenges and opportunities. Breast Cancer Res Treat, 75, S61-5, discussion S57-9.
  12. Hsieh HL, Wang HH, Wu WB, et al (2010). Transforming growth factor-${\beta}$1 induces matrix metalloproteinase-9 and cell migration in astrocytes: roles of ROS-dependent ERK-and JNK-NF-${\kappa}B$ pathways. J Neuroinflammation, s, 88.
  13. Hedges JC, Dechert MA, Yamboliev IA, et al (1999).A role for p38(MAPK)/HSP27 pathway in smooth muscle cell migration. J Biol Chem, 274, 24211-9.
  14. Helfman DM, Pawlak G (2004). Myosin light chain kinase and acto-myosin contractility modulate activation of theERK cascade downstream of oncogenic Ras. J Cell Biochem, 95, 1069-80.
  15. IIunga K, Nishiura R, Inada H (2004). Co-stimulation of human breast cancer cells with transforming growth factor-beta and tenascin-C enhances matrix metalloproteinase-9 expression and cancer cell invasion. Int J Exp Pathol, 85, 373-9
  16. Imamura T, Hikita A, Inoue Y (2012). The roles of TGF-${\beta}$ signaling in carcinogenesis and breast cancer metastasis. Breast Cancer, 19, 118-24.
  17. Geiger TR, Peeper DS (2009). Metastasis mechanisms. Biochim Biophys Acta, 1796, 293-308.
  18. Kim HS, Luo L, Pflugfelder SC, Li DQ (2005). Doxycycline inhibits TGF-beta1-induced MMP-9 via Smad and MAPK pathways in human corneal epithelial cells. Invest Ophthalmol Vis Sci, 46, 840-8.
  19. Na D, Lv ZD, Liu FN, et al (2010). Transforming growth factor beta1 produced in autocrine/ paracrine manner affects the morphology and function of mesothelial cells and promotes peritoneal carcinomatosis. Int J Mol Med, 26, 325-32.
  20. Harhra NA, Basaleem HO (2012). Trends of breast cancer and its management in the last twenty years in aden and adjacent governorates, yemen. Asian Pac J Cancer Prev, 13, 4347-51
  21. Park J, Ayyappan V, Bae EK, et al (2008). Curcumin in combination with bortezomib synergistically induced apoptosis in human multiple myeloma U266 cells. Mol Oncol, 2, 317-26.
  22. Perera M, Tsang CS, Distel RJ, et al (2010). TGF-beta1 interactome: metastasis and beyond. Cancer Genomics Proteomics, 7, 217-29.
  23. Porter PL(2009). Global trends in breast cancer incidence and mortality. Salud Publica Mex, 51, S141-6.
  24. Safina A, Vandette E, Bakin AV (2007). ALK5 promotes tumor angiogenesis by upregulating matrix metalloproteinase-9 in tumor cells. Oncogene, 26, 2407-22.
  25. Sanchez-Zamorano LM, Flores-Luna L, Angeles-Llerenas A et al (2011). Healthy lifestyle on the risk of breast cancer. Cancer Epidemiol Biomarkers Prev, 20, 912-22.
  26. Santibanez JF, Guerrero J, Quintanilla M, et al (2002). Transforming growth factor-beta1 modulates matrix metalloproteinase-9 production through the Ras/MAPK signaling pathway in transformed keratinocytes. Biochem Biophys Res Commun, 16, 267-73.
  27. Santibanez JF, Quintanilla M, Martinez J (2000). Genistein and curcumin block TGF-beta 1-induced u-PA expression and migratory and invasive phenotype in mouse epidermal keratinocytes. Nutr Cancer, 37, 49-54.
  28. Serra R, Crowley MR (2005). Mouse models of transforming growth factor beta impact in breast development and cancer. Endocr Relat Cancer, 12, 749-60.
  29. Smith AL, Robin TP, Ford HL (2012). Molecular Pathways: Targeting the TGF-beta Pathway for Cancer Therapy. Clin Cancer Res, 18, 4514-21.
  30. Smith MR, Gangireddy SR, Narala VR, et al (2010). Curcumin inhibits fibrosis-related effects in IPF fibroblasts and in mice following bleomycin-induced lung injury. Am J Physiol Lung Cell Mol Physiol, 298, L616-25.
  31. Srinivasan R, Forman S, Quinlan RA, et al (2008).Regulation of contractility by Hsp27 and Hic-5 in rat mesenteric small arteries. Am J Physiol Heart Circ Physiol, 294, H961-9.
  32. Szuster-Ciesielska A, Plewka K, Daniluk J (2011). Betulin and betulinic acid attenuate ethanol-induced liver stellate cell activation by inhibiting reactive oxygen species (ROS), cytokine (TNF-alpha, TGF-beta) production and by influencing intracellular signaling. Toxicology, 280, 152-63.
  33. Yan G, Graham K, Lanza-Jacoby S (2012). Curcumin enhances the anticancer effects of trichostatin a in breast cancer cells. Mol Carcinog.
  34. Yao QY, Xu BL, Wang JY, et al (2012). Inhibition by curcumin of multiple sites of the transforming growth factor-beta1 signalling pathway ameliorates the progression of liver fibrosis induced by carbon tetrachloride in rats. BMC Complement Altern Med, 12, 156.
  35. Ye B, Jiang LL, Xu HT, et al (2012). Expression of PI3K/AKT pathway in gastric cancer and its blockade suppresses tumor growth and metastasis. Int J Immunopathol Pharmacol, 25, 627-36.
  36. Yodkeeree S, Ampasavate C, Sung B, et al (2010). curcumin suppresses migration and invasion of MDA-MB-231 humanbreast cancer cell line. Eur J Pharmacol, 627, 8-15.
  37. Zayani Y, Allal-Elasmi M, Jacob MP, et al (2012).Abnormal circulating levels of matrix metalloprotei-nases and their inhibitors in diabetes mellitus. Clin La, 58, 779-85.
  38. Zhang SS, Gong ZJ, Li WH, et al (2012). Antifibrotic effect of curcumin in TGF-beta 1-induced myofibroblasts from human oral mucosa. Asian Pac J Cancer Pre, 13, 289-94.
  39. Zhang YE (2009). Non-Smad pathways in TGF-beta signaling. Cell Res, 19, 128-39.

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