Overexpression of S100P in the hormone sensitive parental sellekchem MCF 7 cells significantly Inhibitors,Modulators,Libraries increased resistance to tamoxifen. The mechanism of S100P action may involve its interaction with the receptor RAGE, leading to sustained survival and proliferation. Proteomic analysis of MCF 7 TamR cells also revealed a critical phenotypic transformation of the cells towards an increased migratory capacity, consistent with most clinical outcomes where tumor invasion and metastasis follow the acquired hormone resistance in patients. The enhanced cell motility in the tamoxifen resistant cells appeared to be driven by the cytoskeletal dynamics where Inhibitors,Modulators,Libraries S100P played an important role. This was supported by the observation that overexpressing S100P in MCF 7 cells significantly increased cell migration.

Additional evi dence Inhibitors,Modulators,Libraries comes from proteomic data where up regulation of multiple proteins Inhibitors,Modulators,Libraries in a coordinated signaling network may regulate the actin cytoskeleton dynamics as depicted in our proposed pathway model. Specifically, we observed the up regulation of EphA2, RhoA, ITGB1, vinculin, ezrin, and radixin, which are key proteins contributing to the increased cell motility in a tamoxifen resistant pheno type by promoting actin fiber polymerization, filopodia formation, and cell contractability. Osteoarthritis is the most common arthritis, char acterized by progressive loss of articular cartilage, sub chondral bone remodeling, and synovial inflammation, leading to debilitating joint pain Inhibitors,Modulators,Libraries and functional limita tion. The underlying pathophysiologic process of cartilage destruction in OA has not been completely elucidated.

Inflammation is believed to be implicated in the OA pathogenesis, even in early stages, by shifting the balance from the anabolic toward the catabolic state with gradually progressive cartilage loss. In currently OA, chon drocytes, the only cells residing in cartilage, are a target of catabolic cytokines, including interleukin 1B, tumor necrosis factor, and IL 6. IL 1B in par ticular has been considered a key amplifier and perpetu ator of cartilage damage because it suppresses matrix protein synthesis and induces matrix degrading enzymes and other proinflammatory cytokines, including IL 6. However, postsurgical or spontaneous OA development is paradoxically accelerated in IL 1B or IL 6 knockout mice, suggestive of their intricate role in cartilage biology, the proinflammatory cytokines might slow the OA pro gression via yet unknown mechanisms. Suppressors of cytokine signaling belong to a protein family that is composed of eight SH2 containing proteins and forms E3 ubiquitin ligase complexes to de grade target proteins by proteasomes.