Abstract 2457: Laminin receptor cross-talk stimulates receptor internalization and migration of human prostate cancer cells

• Published in: Cancer research (Chicago, Ill.) Ill.), 2012-04, Vol.72 (8_Supplement), p.2457-2457
• Main Authors: Anderson, Todd A., Gard, Jaime MC, Sroka, Isis C., Strautman, Stephanie R., Morrissey, Colm, Knudsen, Beatrice S., Cress, Anne E.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2012-2457

Integrin cell adhesion receptors are internalized and recycled to the plasma membrane during cellular migration. The laminin binding A3B1 and A6B1 integrin receptors are differentially expressed on prostate tumor cells in Gleason grades 3-5 as detected in biopsy and prostatectomy specimens. The A6 integrin exists as a full length form or as a pro-metastatic variant, A6pB1, a receptor form missing the extracellular laminin binding domain via the action of the serine protease, uPA. The objective of this study is to determine whether internalization of the A6 integrin occurs in human bone metastatic lesions and whether cross-talk between the laminin receptors A6B1, A6pB1 and A3B1 modifies their respective internalization rates. In a tissue microarray of 185 metastatic prostate cancers from 45 patients, approximately 70% of bone metastases expressed A6B1 on tumor plasma membrane and/or within the cytoplasm. The A6 and A6p integrins in DU145 cells are constitutively internalized with a biological half life of approximately 30 minutes as compared to 60 minutes for A3 or 20 minutes for the unrelated transferrin receptor. Increasing production of A6pB1 by supplying exogenous uPA stimulated A3 internalization. Conversely, blockage of A6pB1 production using an A6 specific antibody (J8H) decreased A3 internalization. Targeted depletion of the A3 integrin increased DU145 cell migration that was dependent upon A6 integrin as detected by antibody blocking experiments using J8H (A6 specific) and AIIB2 (B1 specific). Analysis of transcriptomic data from prostate cancer xenografts, revealed three different candidate receptor recycling genes that significantly correlated with the loss of membrane and increase in cytoplasmic expression. Taken together, these data indicate that cross-talk between A6B1 and A3B1 modifies their internalization rates and prostate tumor cell migration. This suggests that successful therapeutic targeting of metastasizing prostate cancer cells may depend upon coordinated targeting of both receptors and the recycling machinery. Current work is to determine the involvement of candidate recycling genes in the biological control of laminin binding integrins in human prostate cancer. (Supported in part by NIH grants P30CA023074, 1RO1 CA159406 and the TACMASS core service of the University of Arizona Cancer Center). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer R