RESUMO
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.
Assuntos
Carcinoma/patologia , Transformação Celular Neoplásica/metabolismo , Adesões Focais/metabolismo , Proteínas dos Microfilamentos/metabolismo , Fosfoproteínas/metabolismo , Neoplasias da Próstata/patologia , Animais , Carcinoma/metabolismo , Adesão Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Regulação para Baixo , Matriz Extracelular/patologia , Adesões Focais/genética , Humanos , Integrinas/metabolismo , Masculino , Camundongos , Camundongos Nus , Proteínas dos Microfilamentos/genética , Mutação , Fosfoproteínas/genética , Neoplasias da Próstata/metabolismo , Proteínas Tirosina Quinases/metabolismo , Regulação para CimaRESUMO
The dietary stilbene resveratrol is a major constituent of a variety of edible plant products, including grapes and peanuts. Resveratrol has been identified as an excellent candidate cancer chemopreventive, based on its safety and efficacy in animal models of carcinogenesis. Resveratrol is a prototype of a plethora of bioactive polyphenols in the food supply that has just begun to be mined for cancer preventive agents. For example, polyphenolic grapeseed fractions were shown recently to potently antagonize chemical carcinogenesis. Taking into consideration that the identification of resveratrol as a cancer preventive agent is largely owed to its high abundance in nature (e.g., it accounts for 5-10% of the grapeskin biomass), it is logical to expect that naturally occurring stilbenes that are superior to resveratrol in their cancer preventive properties await identification. Thus, resveratrol may represent the tip of the iceberg of a broad class of stilbene and related polyphenolic natural products that include safe and highly effective agents for cancer prevention. We hypothesize that resveratrol may be especially suitable as a lead agent for prostate cancer prevention given its ability to: 1) inhibit each stage of multistage carcinogenesis, 2) scavenge incipient populations of androgen-dependent prostate cancer cells through androgen receptor antagonism, and 3) scavenge incipient populations of androgen-independent prostate cancer cells by short-circuiting the epidermal growth factor-receptor (EGFR)-dependent autocrine loops in the cancer cells.