Reorganization of the integrin alpha2 subunit controls cell adhesion and cancer cell invasion in prostate cancer.
The mechanisms of invasion and metastasis are poorly understood. Our previous studies demonstrated that cancer cell invasion may result from reorganization of membrane molecules, thereby initiating signaling pathways. To increase our understanding on how cancer cells govern metastases we studied the established LNCaP prostate cancer progression model. Herein we show that the bone metastatic derivative cell line, C4-2B, displays changes in adhesion to collagen type I and invasion into collagen type I. Moreover, we found that these changes were concomitant with activation of the FAK/src/paxillin/Rac/JNK signaling pathway and increased activity of matrix metalloproteinases (MMPs)-2 and -9. Inhibition of src and JNK resulted in inhibition of adhesion and invasion, and deactivation of the signaling molecules in the identified pathway as well as reduced activity of MMPs. Additionally, we found a pivotal role for the integrin alpha2 subunit since lateral redistribution and clustering were responsible for activation of the downstream signaling and function blocking of the integrin alpha2 subunit resulted in poor adhesion and inhibition of invasion. In conclusion, our results suggest that invasion of prostate cancer cells can be ascribed to reorganization and clustering of integrin alpha2 subunits, resulting in activation of associated FAK/src/paxillin/Rac/JNK, leading to increased activity of MMPs and thus invasion.
Van Slambrouck
Severine
S
Department of Chemistry, Laboratory of Biochemical and Biomedical Research, New Mexico Tech, Socorro, NM 87801, USA. severine@nmt.edu
Jenkins
Aaron R
AR
Romero
Anntherese E
AE
Steelant
Wim F A
WF
D015153:Blotting, Western; D002448:Cell Adhesion; D002465:Cell Movement; D024042:Collagen Type I / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D039421:Integrin alpha2 / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D051419:Paxillin / Q000378:metabolism; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
D024042:Collagen Type I; D039421:Integrin alpha2; C496061:PXN protein, human; D051419:Paxillin; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D019061:src-Family Kinases; D048670:MAP Kinase Kinase 4; D020782:Matrix Metalloproteinases; D020744:rac GTP-Binding Proteins