CCR9-CCL25 interactions promote cisplatin resistance in breast cancer cell through Akt activation in a PI3K-dependent and FAK-independent fashion

<p>Abstract</p> <p>Background</p> <p>Chemotherapy heavily relies on apoptosis to kill breast cancer (BrCa) cells. Many breast tumors respond to chemotherapy, but cells that survive this initial response gain resistance to subsequent treatments. This leads to aggressive cell variants with an enhanced ability to migrate, invade and survive at secondary sites. Metastasis and chemoresistance are responsible for most cancer-related deaths; hence, therapies designed to minimize both are greatly needed. We have recently shown that CCR9-CCL25 interactions promote BrCa cell migration and invasion, while others have shown that this axis play important role in T cell survival. In this study we have shown potential role of CCR9-CCL25 axis in breast cancer cell survival and therapeutic efficacy of cisplatin.</p> <p>Methods</p> <p>Bromodeoxyuridine (BrdU) incorporation, Vybrant apoptosis and TUNEL assays were performed to ascertain the role of CCR9-CCL25 axis in cisplatin-induced apoptosis of BrCa cells. Fast Activated Cell-based ELISA (FACE) assay was used to quantify <it>In situ </it>activation of PI3K^p85, Akt^Ser473, GSK-3β^Ser9and FKHR^Thr24in breast cancer cells with or without cisplatin treatment in presence or absence of CCL25.</p> <p>Results</p> <p>CCR9-CCL25 axis provides survival advantage to BrCa cells and inhibits cisplatin-induced apoptosis in a PI3K-dependent and focal adhesion kinase (FAK)-independent fashion. Furthermore, CCR9-CCL25 axis activates cell-survival signals through Akt and subsequent glycogen synthase kinase-3 beta (GSK-3β) and forkhead in human rhabdomyosarcoma (FKHR) inactivation. These results show that CCR9-CCL25 axis play important role in BrCa cell survival and low chemotherapeutic efficacy of cisplatin primarily through PI3K/Akt dependent fashion.</p

Knowledge-guided docking: accurate prospective prediction of bound configurations of novel ligands using Surflex-Dock

Prediction of the bound configuration of small-molecule ligands that differ substantially from the cognate ligand of a protein co-crystal structure is much more challenging than re-docking the cognate ligand. Success rates for cross-docking in the range of 20–30 % are common. We present an approach that uses structural information known prior to a particular cutoff-date to make predictions on ligands whose bounds structures were determined later. The knowledge-guided docking protocol was tested on a set of ten protein targets using a total of 949 ligands. The benchmark data set, called PINC (“PINC Is Not Cognate”), is publicly available. Protein pocket similarity was used to choose representative structures for ensemble-docking. The docking protocol made use of known ligand poses prior to the cutoff-date, both to help guide the configurational search and to adjust the rank of predicted poses. Overall, the top-scoring pose family was correct over 60 % of the time, with the top-two pose families approaching a 75 % success rate. Correct poses among all those predicted were identified nearly 90 % of the time. The largest improvements came from the use of molecular similarity to improve ligand pose rankings and the strategy for identifying representative protein structures. With the exception of a single outlier target, the knowledge-guided docking protocol produced results matching the quality of cognate-ligand re-docking, but it did so on a very challenging temporally-segregated cross-docking benchmark