Abstract
AbstractTalin1 is an integrin regulatory protein that mediates integrin interactions with the extracellular matrix (ECM). This study investigated the significance of talin1 in prostate cancer progression to metastasis in vitro and in vivo. Talin1 overexpression enhanced prostate cancer cell adhesion, migration and invasion by activating survival signals and anoikis resistance. ShRNA-mediated talin1 loss led to a significant suppression of prostate cancer cell migration and transendothelial invasion in vitro and a significant inhibition of prostate cancer metastasis in vivo. Talin1 regulates cell survival signals via phosphorylation of focal adhesion kinase (FAK) and AKT. Targeting AKT activation led to a significant reduction of talin1-mediated prostate cancer cell invasion. Furthermore, talin1 expression was determined by immunostaining in prostate tissue from the TRAMP mouse model and in human prostate cancer specimens. Talin1 levels directly correlated with prostate tumor progression to metastasis in TRAMP mice. Talin1 profiling in human prostate specimens revealed a significantly higher expression of cytoplasmic talin1 in metastatic tissue compared to primary prostate tumors and benign prostate tissue (P<0.0001). This evidence suggests a potential value for talin1 as a marker of prostate cancer metastasis and implies that disrupting talin1 mediated signaling may have therapeutic significance in the treatment of metastatic disease.
Highlights
Cancer metastasis is a multistep and complex process that involves dissociation of the tumor cells from the organ of origin, degradation of the extracellular matrix (ECM), cell migration, anchorage-independent growth, apoptosis evasion, angiogenesis, invasion of surrounding tissues, cell adhesion, movement and colonization to distant sites in the body[1]
Our results indicate that talin[1] engages the PI3-K/AKT signaling as the intracellular survival mechanism to confer anoikis resistance and promote invasion of human prostate cancer cells
Overexpression of talin[1] significantly increased both the adhesion (Fig. 1B) and migration potential of prostate cancer cells compared to vector control cells (Fig. 1, panels C, D)
Summary
Cancer metastasis is a multistep and complex process that involves dissociation of the tumor cells from the organ of origin, degradation of the extracellular matrix (ECM), cell migration, anchorage-independent growth, apoptosis evasion, angiogenesis, invasion of surrounding tissues, cell adhesion, movement and colonization to distant sites in the body[1]. Androgen-independent prostate cancer cells become resistant due to roadblocks in apoptosis and depending on the interactions with the tumor microenvironment, acquire invasive and metastatic properties[2]. Both tumor epithelial and endothelial cells require attachment to the ECM for survival; commonly upon loss of adhesion, cells undergo detachment-induced cell death, or anoikis. Integrin-linked kinase (ILK) has been recognized as contributor to anoikis resistance via its ability to regulate several integrin-mediated cellular processes including cell adhesion, fibronectin-ECM assembly and anchorage-dependent cell growth[6,7,8]
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