AFAP-110 is overexpressed in prostate cancer and contributes to tumorigenic growth by regulating focal contacts.

Abstract

The actin filament-associated protein AFAP-110 is an actin cross-linking protein first identified as a substrate of the viral oncogene v-Src. AFAP-110 regulates actin cytoskeleton integrity but also functions as an adaptor protein that affects crosstalk between Src and PKC. Here we investigated the roles of AFAP-110 in the tumorigenic process of prostate carcinoma. Using immunohistochemistry of human tissue arrays, we found that AFAP-110 was absent or expressed at very low levels in normal prostatic epithelium and benign prostatic hyperplasia but significantly increased in prostate carcinomas. The level of AFAP-110 in carcinomas correlated with the Gleason scores. Downregulation of AFAP-110 in PC3 prostate cancer cells inhibited cell proliferation in vitro and tumorigenicity and growth in orthotopic nude mouse models. Furthermore, downmodulation of AFAP-110 resulted in decreased cell-matrix adhesion and cell migration, defective focal adhesions, and reduced integrin beta1 expression. Reintroduction of avian AFAP-110 or a mutant disabling its interaction with Src restored these properties. However, expression of an AFAP-110 lacking the PKC-interacting domain failed to restore properties of parental cells. Thus, increased expression of AFAP-110 is associated with progressive stages of prostate cancer and is critical for tumorigenic growth, in part by regulating focal contacts in a PKC-dependent mechanism.

• Authors: Jing Zhang, Serk In Park, Marlene C Artime, Justin M Summy, Ami N Shah, Joshua A Bomser, Andrea Dorfleutner, Daniel C Flynn, Gary E Gallick
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 117 Issue 10 Pg. 2962-73 (Oct 2007) ISSN: 0021-9738 [Print] United States
• PMID: 17885682 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• AFAP 110
• Integrins
• Microfilament Proteins
• Phosphoproteins
• Protein-Tyrosine Kinases

Topics

• Animals
• Carcinoma (metabolism, pathology)
• Cell Adhesion (genetics)
• Cell Line, Tumor
• Cell Movement (genetics)
• Cell Proliferation
• Cell Transformation, Neoplastic (metabolism)
• Down-Regulation
• Extracellular Matrix (pathology)
• Focal Adhesions (genetics, metabolism)
• Humans
• Integrins (metabolism)
• Male
• Mice
• Mice, Nude
• Microfilament Proteins (genetics, metabolism)
• Mutation
• Phosphoproteins (genetics, metabolism)
• Prostatic Neoplasms (metabolism, pathology)
• Protein-Tyrosine Kinases (metabolism)
• Up-Regulation