Endothelin Receptors

The PAK proteins have important roles in regulation of the cofilin pathway and actin cytoskeleton as well as other cellular functions including proliferation and apoptosis [46]

The PAK proteins have important roles in regulation of the cofilin pathway and actin cytoskeleton as well as other cellular functions including proliferation and apoptosis [46]. with a cofilin expressing vector, ALN treatment did not decrease cellular cofilin levels and migration as in mock transfected cells. ALN also reduced immunohistochemical staining of cofilin in PC-3 xenografts. Our results suggest that reduction of cofilin has an important role in ALN-induced disruption of the actin cytoskeleton and inhibition of the PC-3 cell motility and invasion. These data also support the idea that the nitrogen-containing bisphosphonates could be efficacious in inhibition of prostate cancer invasion and metastasis, if delivered in a pharmacological formulation accessible to the tumors. N-BPs also have immunomodulatory [20C22], apoptotic, antimetastatic and tumor growth inhibiting effects [17, 23, 24]. Regulation of actin cytoskeleton is critical for cell motility [25, 26]. The reorganization of the actin cytoskeleton is essential for cancer cell migration and invasion, and for epithelial-mesenchymal transition (EMT), where epithelial cancer cells acquire more motile mesenchymal properties [27, 28]. Actin filaments are built of monomers that polymerize into a double-helix structure [26]. Cofilin is a key regulator of actin cytoskeleton, enhancing the severing of actin filaments and providing actin monomers CRF (human, rat) Acetate for the polymerization of new filaments [29]. The cofilin pathway has been shown to be critically involved in the regulation of tumor cell migration and invasion [30C32]. Constitutively active cofilin advanced PC-3 cell invasion and lung metastasis in nude mice bearing PC-3 cell xenografts [33]. Besides its major role in modulation of actin dynamics and migration/invasion, cofilin has recently been shown to have many other cellular actions, such an involvement in induction of apoptosis and the maintenance of nuclear structure and functions [32]. In addition, mitochondrial translocation of cofilin was found to be involved in TGF beta-induced apoptosis of prostate cancer cells [33]. The activity of cofilin is regulated by phosphorylation-dephosphorylation reactions, interaction with phosphatidylinositol-4,5-bisphosphate at the plasma membrane or binding to cortactin. Phosphorylation of cofilin at Ser 3 by LIM or TES kinases inactivates the protein, and dephosphorylation at Ser 3 by SSH (slingshot) and some other phosphatases activates it, which reactions primarily determine cofilin regulation of actin dynamics [31, 32]. Besides modulation of cofilin protein and protein interactions, cofilin overexpression, associated with increased activity, has been reported in several cancers. In a prostate cancer patient cohort, cofilin levels were increased and they were significantly higher Alfuzosin HCl in metastases than in primary tumors [33]. Cofilin level was also increased in bladder cancer [34], and in ovarian [35] and Alfuzosin HCl pancreatic cancer [36] overexpression of cofilin was associated with poor prognosis. In non-small-cell lung cancer (NSCLC) high cofilin Alfuzosin HCl level correlated with Alfuzosin HCl poor outcome and cisplatin treatment resistance [37]. Of other proteins modulating actin cytoskeleton, p21-associated kinases (PAK) activate LIM kinase and have wide effects on cancer cell migration and invasion as well as proliferation and survival [27, 31, 38, 39]. Focal adhesion kinase (FAK), paxillin and integrins are focal adhesion-associated regulatory proteins which modulate actin dynamics and cytoskeletal organization in the initiation of cell migration [40]. In addition to ALN-induced changes in F-actin organization in prostate cancer cells [6, 13], zoledronate has been demonstrated to inhibit the expression of alphavbeta3 and alphavbeta5 integrins in endothelial cells [41] and to induce detachment of prostate cancer cells in association with FAK dephosphorylation [42]. In this study, we investigated the mechanisms by which ALN.