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 
May 31, 2021
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 . 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 . 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 . 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 . 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 . In addition, mitochondrial translocation of cofilin was found to be involved in TGF beta-induced apoptosis of prostate cancer cells . 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 . Cofilin level was also increased in bladder cancer , and in ovarian  and Alfuzosin HCl pancreatic cancer  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 . 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 . 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  and to induce detachment of prostate cancer cells in association with FAK dephosphorylation . In this study, we investigated the mechanisms by which ALN.