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.
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.
Department of Food and Environmental Sciences, Division of Nutrition, University of Helsinki, Helsinki, Finland.|University College London, Ludwig Institute for Cancer Research, London, UK.
Anne-Maria
AM
Pajari
Department of Food and Environmental Sciences, Division of Nutrition, University of Helsinki, Helsinki, Finland.
Essi
E
Päivärinta
Department of Biological and Environmental Science / Nanoscience Center, University of Jyväskylä, Jyväskylä, Finland.
Lassi
L
Paavolainen
Department of Food and Environmental Sciences, Division of Nutrition, University of Helsinki, Helsinki, Finland.
Elina
E
Vaara
Department of Food and Environmental Sciences, Division of Food Chemistry, University of Helsinki, Helsinki, Finland.
Tuuli
T
Koivumäki
Randall Division of Cell & Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London, UK.
Ritu
R
Garg
Department of Food and Environmental Sciences, Division of Nutrition, University of Helsinki, Helsinki, Finland.
Anu
A
Heiman-Lindh
Department of Food and Environmental Sciences, Division of Nutrition, University of Helsinki, Helsinki, Finland.
Marja
M
Mutanen
Department of Biological and Environmental Science / Nanoscience Center, University of Jyväskylä, Jyväskylä, Finland.
Varpu
V
Marjomäki
University College London, Ludwig Institute for Cancer Research, London, UK.|Randall Division of Cell & Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London, UK.
Anne J
AJ
Ridley
D000230:Adenocarcinoma / Q000473:pathology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D003110:Colonic Neoplasms / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects; D017228:Hepatocyte Growth Factor; D006801:Humans; D047348:Hydrolyzable Tannins / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism; D010936:Plant Extracts / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D065856:Rubus
D000970:Antineoplastic Agents; D047348:Hydrolyzable Tannins; D010936:Plant Extracts; C013515:ellagitannin; D017228:Hepatocyte Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
Met receptor; Min mouse; cell migration; colorectal cancer; ellagitannins