Osteopontin induces beta-catenin signaling through activation of Akt in prostate cancer cells.
Secretion of osteopontin (OPN) by cancer cells is a known mediator of tumorigenesis and cancer progression in both experimental and clinical studies. Our work demonstrates that OPN can activate Akt, an important step in cancer progression. Both ILK and PI3K are integral proteins in the OPN/Akt pathway, as inhibition of either kinase leads to a loss of OPN-mediated Akt activation. Subsequent to OPN-induced Akt activation, we observe inactivation of GSK-3beta, a regulator of beta-catenin. Osteopontin stimulation leads to an overall increase in beta-catenin protein levels with a resultant transfer of beta-catenin to the nucleus. Through the nuclear import of beta-catenin, OPN increases both the transcription and protein levels of MMP-7 and CD44, which are known TCF/LEF transcription targets. This work describes an important aspect of cancer progression induced by OPN.
Department of Oncology and Diagnostic Sciences, Dental School, University of Maryland, Baltimore, MD 21201, USA.
Brian W
BW
Robertson
Meenakshi A
MA
Chellaiah
D021581:Active Transport, Cell Nucleus / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D008297:Male; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism; D008954:Models, Biological; D053495:Osteopontin / Q000494:pharmacology / Q000502:physiology*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051820:TCF Transcription Factors / Q000378:metabolism; D014162:Transfection; D051176:beta Catenin / Q000378:metabolism*; D000099200:Scaffold Protein ILK
D004791:Enzyme Inhibitors; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D018960:Hyaluronan Receptors; D020783:Matrix Metalloproteinase 7; D053495:Osteopontin; D018129:Phosphatidylinositol Phosphates; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D051820:TCF Transcription Factors; D051176:beta Catenin; D000099200:Scaffold Protein ILK; C497483:CD44 protein, human; C055525:phosphatidylinositol 3-phosphate; C000605506:GSK3B protein, human; C060932:MMP7 protein, human