Src activity alters alpha3 integrin expression in colon tumor cells.
Src kinase has been linked to increased motility in the progression and metastasis of human colon cancer, although the mechanisms are not fully understood. Integrins are involved in metastasis by mediating attachment and migration of cells, as well as through transducing signals. This study examines the link between Src and integrin activity in the metastatic process in colon cancer cells. To determine Src involvement in integrin expression, the human colon cancer cell line, HCT116, was transfected with an activated Src construct and assayed for its ability to attach to and migrate across collagen and laminin. These cells attached more readily and migrated less rapidly on the extracellular matrix (ECM) than did cells transfected with empty vector. Examination of integrin levels showed a decrease in the alpha3 subunit in Src transfected cells as well as decreased cell surface localization of alpha3 integrin. The downregulation of alpha3 integrin was reversed by inhibition of Src and by inhibition of MAP kinase. Inhibition of alpha3 integrin using shRNA resulted in decreased MMP7 secretion, a possible cause of decreased invasion with low alpha3 integrin expression. This study shows that Src overexpression downregulates alpha3 integrin total protein expression and localization to the cell surface of HCT116 colon cancer cells. This indicates that Src activity may enhance metastasis by altering alpha3 integrin expression.
Department of Medicine, Penn State Hershey Cancer Institute, H072, The Pennsylvania State University College of Medicine, 500 University Drive, Box 850, Hershey, PA 17033, USA.
Christina Leah B
CL
Kline
Thomas L
TL
Olson
Rosalyn B
RB
Irby
D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D002867:Chromones / Q000494:pharmacology; D003110:Colonic Neoplasms; D015536:Down-Regulation / Q000502:physiology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D039422:Integrin alpha3 / Q000096:biosynthesis*; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
D002867:Chromones; D016326:Extracellular Matrix Proteins; D005419:Flavonoids; D039422:Integrin alpha3; D009025:Morpholines; D011728:Pyridones; D011743:Pyrimidines; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019061:src-Family Kinases; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D020783:Matrix Metalloproteinase 7; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; C410732:PD 180970