In addition, whether PHB plays any role in RAS ERK driven pancreatic cancer remains undetermined. Rocaglamide, a naturally occurring compound, has a unique cyclopenta benzofuran skeleton and is isolated from the medicinal plants selleck chemical belonging to genus Aglaia. which are traditionally used in folk medicine for the treatment of coughs, injuries, asthma, and inflammatory skin diseases. More recently, Polier et Inhibitors,Modulators,Libraries al. carried out affinity chromatography coupled mass spectrometry to identity PHB as the direct target of RocA in leukemic cells. Importantly, they also revealed the mechanism in which binding of RocA to PHB prevents CRAF PHB interactions, thus leading to impaired ERK1 2 activation in leukemic cells. Therefore, RocA may be used to target protein protein interactions rather than the catalytic Inhibitors,Modulators,Libraries kinase domain.

In the present study, we unravel a new therapeutic paradigm to inhibit RAS driven pancreatic tumors by blocking the interactions of PHB scaffold CRAF kinase. Furthermore, Inhibitors,Modulators,Libraries RocA suppresses ERK activity and blocks Inhibitors,Modulators,Libraries in vitro and in vivo growth and metastasis of pancreatic cancer cells that are addicted to the ERK pathway. Thus, the regulation of RAS RAF ERK pathway by targeting the PHB CRAF interaction introduces a novel potential therapeutic approach for ERK driven pancreatic cancer. Results Expression and localization of PHB in pancreatic cancer cells and tissue To investigate the role of PHB in pancreatic cancer cells, we first chose two human pancreatic cancer cell lines, AsPC 1 and Capan 2. Interestingly, AsPC 1 cells grew as single cells, whereas Capan 2 cells exhibited tiny islands of densely packed cells.

Add itionally, AsPC 1 cells exhibited much higher growth and migration capacities than those of Capan 2 cells. RT PCR showed a difference in PHB mRNA expression levels, revealing higher expression in AsPC Inhibitors,Modulators,Libraries 1 cells than that in Capan 2 cells. In agree ment with RT PCR data, immunoblot analysis also demon strated high expression of PHB protein in AsPC 1 cells, but little expression in Capan 2 cells. Intriguingly, localization of PHB in AsPC 1 cells was mainly in the plasma membrane and cytosol, whereas its localization was uniform in Capan 2 cells. This result indicated that the observed phenotypes may correlate with the expression and localiza tion of PHB protein. Therefore, AsPC 1 cells were chosen to investigate the biological properties of PHB in pancre atic cancer both in vitro and in vivo.

We next assessed PHB expression in pancreatic tissue. PHB protein was weakly expressed in 63. 6% of normal pancreas samples. However, PHB protein was strongly expressed in 58. 7% of PDAC samples. Taken together, these results show that selleck chem PHB, which becomes more pronounced with pancreatic cancer malig nancy, may serve as a therapeutic target in pancreatic cancer.