Ellagitannin-rich cloudberry inhibits hepatocyte growth factor induced cell migration and phosphatidylinositol 3-kinase/AKT activation in colon carcinoma cells and tumors in Min mice
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Anne-Maria Pajari1,2, Essi Päivärinta1, Lassi Paavolainen3, Elina Vaara1, Tuuli Koivumäki4, Ritu Garg5, Anu Heiman-Lindh1, Marja Mutanen1, Varpu Marjomäki3, Anne J. Ridley2,5
1Department of Food and Environmental Sciences, Division of Nutrition, University of Helsinki, Helsinki, Finland
2University College London, Ludwig Institute for Cancer Research, London, UK
3Department of Biological and Environmental Science / Nanoscience Center, University of Jyväskylä, Jyväskylä, Finland
4Department of Food and Environmental Sciences, Division of Food Chemistry, University of Helsinki, Helsinki, Finland
5Randall Division of Cell & Molecular Biophysics, King’s College London, New Hunt’s House, Guy’s Campus, London, UK
Anne-Maria Pajari, email: [email protected]
Anne J. Ridley, email: [email protected]
Keywords: colorectal cancer, cell migration, Met receptor, ellagitannins, Min mouse
Received: November 06, 2015 Accepted: May 16, 2016 Published: May 30, 2016
Berries have been found to inhibit colon carcinogenesis in animal models, and thus represent a potential source of compounds for prevention and treatment of colorectal cancer. The mechanistic basis for their effects is not well understood. We used human colon carcinoma cells and Min mice to investigate the effects of ellagitannin-rich cloudberry (Rubus chamaemorus) extract on cancer cell migration and underlying cell signaling. Intrinsic and hepatocyte growth factor (HGF) -induced cell motility in human HT29 and HCA7 colon carcinoma cells was assessed carrying out cell scattering and scratch wound healing assays using time-lapse microscopy. Activation of Met, AKT, and ERK in cell lines and tumors of cloudberry-fed Min mice were determined using immunoprecipitation, Western blot and immunohistochemical analyses. Cloudberry extract significantly inhibited particularly HGF-induced cancer cell migration in both cell lines. Cloudberry extract inhibited the Met receptor tyrosine phosphorylation by HGF and strongly suppressed HGF-induced AKT and ERK activation in both HT29 and HCA7 cells. Consistently, cloudberry feeding (10% w/w freeze-dried berries in diet for 10 weeks) reduced the level of active AKT and prevented phosphoMet localization at the edges in tumors of Min mice. These results indicate that cloudberry reduces tumor growth and cancer cell motility by inhibiting Met signaling and consequent activation of phosphatidylinositol 3-kinase/AKT in vitro and in tumors in vivo. As the Met receptor is recognized to be a major target in cancer treatment, our results suggest that dietary phytochemicals may have therapeutic value in reducing cancer progression and metastasis.
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