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No description available.

Hepatitis B virus encoded X protein (HBx) contributes centrally to the pathogenesis of hepatocellular carcinoma (HCC). Aberrant activation of the Hedgehog (Hh) pathway has been linked to cancer. Thus, experiments were designed to test the hypothesis that HBx contributes to HCC via activation of Hh signaling. HBx expression correlated with up-regulation of Hh markers in human liver cancer cell lines, in HBx transgenic mice that developed HCC and in liver samples from HBV infected patients with HCC. The findings in human samples provide clinical validation of those in the HBx transgenic mice (HBxTg), and underscore the relevance of these transgenic mice to disease pathogenesis. Further, blockade of Hh signaling inhibited HBx stimulation of cell migration, anchorage independent growth, HCC tumorigenesis in HBx transgenic mice and tumor growth in xenograft model. These results suggest that the ability of HBx to promote cancer is at least partially dependent upon Hh activation and that activation of Hh signaling appears to be important for the development of HBx associated HCC. HBx also activates pathways that stimulate downstream Hh signaling, such as PI3K/AKT and Ras/Raf/MEK, also referred as non-canonical Hh signaling. Upon canonical Hh inhibition, compensatory activation of these pathways was seen in the presence of HBx in liver cancer cell lines and in HBxTg mice. Individual inhibition of these pathways also down-regulated Gli2 expression in HBx positive cell lines. These data suggests that in addition to canonical Hh signaling, activation of PI3K/AKT and ERK pathways by HBx leads to up-regulation of Gli2 expression in HBV-mediated HCC. This work identifies Hh pathway inhibition as a therapeutic strategy to slow tumor development and this work could lead to combination therapies that target Hh, AKT and ERK pathways, which may prevent or delay the appearance/progression of HCC. / Biology

The field of systems biology has become very popular as a means to deal with cancer as well as other complex biological issues. It enables scientists to gain an insight into difficult conditions through mathematical approaches that have been developed. Prostate cancer is the second leading cause of death among men after skin cancer and its heterogeneity makes it a complex disease. In this study we focus on three pathways known to play crucial roles in the formation of prostate cancer. By using a mathematical model that combines all of them we describe the interactions taking place during signal transduction in the prostate under normal and cancer conditions.

The Hsp70 family of molecular chaperones is essential for protein folding, re-folding misfolded client proteins, clearance of aberrant client proteins, and can also inhibit programmed cell death. There are two major cytosolic members of this family: the constitutive Hsc70, and the inducible Hsp72. Under stress conditions the Hsp70 family protects the cell from protein related damage by the induction of Hsp72. Hsc70 and Hsp72 are highly homologous with minor differences in substrate binding. In cancers, Hsp72 is commonly induced and this induction is thought to aid in cancer cell survival. In these studies we demonstrate the differential regulation of the prosurvival kinase Akt by Hsc70 and Hsp72. We demonstrate that of the two cytosolic forms, Hsp72 is the primary Akt regulator. Using a phenothiazine class inhibitor of Hsp70-family activity, methylene blue, we demonstrate dose dependent decreases in the levels of Akt; produced breast cancer specific cell death. This cell death could be rescued by the use of an Hsp70 family ATPase stimulating compound, SW02. We also demonstrate a similar phenotype with a rhodacyanine class Hsp70 family inhibitor, YM-1, also capable of reducing Akt and causing cancer specific cytotoxicity. The resulting Akt decreases were sufficient to block a tamoxifen-resistance pathway, allowing previously resistant cells to regain sensitivity to tamoxifen. These results demonstrate the capabilities of Hsp70 family inhibitors as potent compounds for the treatment of breast cancer.