However the high concentrations needed to achieve some inhibition

Inhibition appears to be independent of p53 in prostate cancer, multiple myeloma, and colon cancer cells. Moreover, in NCH-51 breast and lung cancer, sensitivity to proteasome inhibition seems to be only partially dependent on p53. Therefore, the degree to which p53 status modulates sensitivity to proteasomal inhibition may be, in fact, cell-type dependent. The relationship between p53 and the proteasome in neuroblastomas also appears to vary depending on the cell line. The SK-N-BE cell line used in the present study was derived from a neuroblastoma patient after chemotherapy and contains a missense mutation which inactivates p53. Our data confirm that the apoptosis induced by MG132 and by the combination of RA/MG132 is independent of p53 in SK-NBE neuroblastoma cells. Hagenbuchner et al. 2010 demonstrated that Bortezomibinduced apoptosis in neuroblastoma cells activates the proapoptotic BH3-only proteins Noxa and Puma and induces repression of the anti-apoptotic Bcl2 family member Bcl-xL. Thus, we assessed the pathways implicated in the apoptotic effects of the proteasome inhibitor MG132 when combined with RA. Proteasome inhibitors, such as Bortezomib or MG132, are well known NF-��B inhibitors. Based on the sub-cellular localization of RelA proteins in our experiments, MG132 blocks NF-��B signalling when administered with RA to SK-NBE neuroblastoma cells. Some forms of retinoic acid produce a reduction in NF-��B activity in human malignant keratinocytes. NF-��B regulates a variety of genes implicated in cell proliferation and cell survival. Therefore, in many different types of human tumors, including high risk neuroblastoma, NF-��B is constitutively active and drives cell proliferation. NFkB is also linked to the immune regulation of neuroblastomas; low levels of NF-kB are associated with reduced expression of MHC-1 complexes. Overexpression of NF-kB p65 together with Interferon Regulatory Factor 1 was able to restore MHC-1 expression and cellular immune complex formation in neuroblastoma cell lines. However, in intestinal cancer, NF-��B signalling enhances Wnt activation and induces dedifferentiation of non-stem cells that acquire tumor-initiating capacity. These observations suggest that NF-��B signalling may be a therapeutic MCE Company Vadimezan target depending on the type of ca

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