AFAP-110 is overexpressed in prostate cancer and contributes to tumorigenic growth by regulating focal contacts.
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.
Zhang
Jing
J
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Park
Serk In
SI
Artime
Marlene C
MC
Summy
Justin M
JM
Shah
Ami N
AN
Bomser
Joshua A
JA
Dorfleutner
Andrea
A
Flynn
Daniel C
DC
Gallick
Gary E
GE
D000818:Animals; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D015536:Down-Regulation; D005109:Extracellular Matrix / Q000473:pathology; D022001:Focal Adhesions / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016023:Integrins / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015854:Up-Regulation
C084510:AFAP 110; D016023:Integrins; D008840:Microfilament Proteins; D010750:Phosphoproteins; D011505:Protein-Tyrosine Kinases