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Molecular targets of bortezomib on adult T-cell leukemia cells

ABSTRACT: BACKGROUND: The molecular mechanism of proteasome inhibitor-mediated anti-cancer activity has been logically hypothesized that the major pathway is inhibition of nuclear factor kappa-B (NF-kB) cascades, however, the precise mechanism is still unclear. Adult T-cell leukemia (ATL) is a fatal neoplasia derived from HTLV-1 infected T lymphocytes exhibiting constitutive activation of NF-kB. AIM: To elucidate the complex molecular mechanism of anti-tumor effect of the proteasome inhibitor, bortezomib in ATL cells, we attempted to perform network-based gene expression profiling. METHODS and RESULTS: Assessment of gene regulation by microarray analysis revealed that down-regulation of genes involved in anti-apoptosis (i.e., BCL2, and IAP5), up-regulation of genes related with apoptosis (i.e., FAF1), heat shock proteins (i.e., HSPA, HSPCA), and oxygen stress (i.e., heme oxygenase-1: HMOX-1). Gene network analysis employing the Bayesian statistical framework also suggests that HMOX-1 which is known as an inducer of reactive oxygen species (ROS), as well as SPARC play an important role in bortezomib-treated ATL cells. The HMOX-1 inhibitor, ZnPP, in addition to bortezomib partially inhibited the apoptotic effect of bortezomib on TaY cells. CONCLUSION: Our results suggest that in addition to the inhibition of NF-kB, bortezomib activated ROS pathway through HMOX-1, and SPARC may participate bortezomib-induced apoptosis, providing novel insight into the bortezomib mediated anti-tumor activity in ATL cells. Keywords: dose response and time course

ORGANISM(S): Homo sapiens

PROVIDER: GSE5794 | GEO | 2007/10/09

SECONDARY ACCESSION(S): PRJNA97157

REPOSITORIES: GEO

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Project description:Background. Heat shock protein 90 (Hsp90) is essential for the stability and the function of many client proteins, such as ERB2, C-RAF, CDK4, HIF-1 aplha and AKT. Recent reports demonstrated that inhibition of Hsp90 modulates multiple functions required for survival of human cancer, such as myeloma (Mitsiades et al, Blood:107, 1092, 2006), however, the precise mechanism of anti-cancer effect of Hsp90 inhibition is still uncertain. Aim. The aim of this study is evaluate the effect of Hsp90 inhibition, and to identify molecular pathways responsible for anti-proliferative effect on ATL cells. Method. For Hsp90 inhibition, Geldanamycin derivates, 17AAG (17-allylamino -17-demethoxygeldanamycin) and 17DMAG (17-(dimethylaminoethylamino) 17-demethoxygeldanamycin) were used in this study. Interleukin 2-independent ATL cell lines (MT-2 and MT-4) and an interleukin 2-dependent ATL cell line (TaY) were incubated, with or without Hsp90 inhibitors. Fresh ATL cells obtained from patients were also used after obtaining informed consent. Cell numbers at 48 h after incubation with or without Hsp90 inhibitors were assessed with the Cell Counting Kit-8 assay (Dojindo Molecular Technologies, Gaithersburg, MD, USA). For detection of apoptosis, we used Annexin V-biotin apoptosis detection kit (Calbiochem, La Jolla, CA, USA). Gene expression analysis was done using a DNA microarray (NCBI Gene expression omnibus; GPL 2531) and statistical analysis was done by a GeneSifter (VizXlabs, Seattle, WA, USA). Results. We found cell death induced by Hsp90 inhibitors in all the 3 ATL cell lines as well as patient specimens. Inhibitory concentration (IC50) of 17AAG in 3 ATL cell lines was 300 to 700 nM, and that of 17DMAG was 150 to 200 nM. Fresh ATL cells obtained from patients were more sensitive for either 17AAG or 17DMAG. Gene expression analysis of ATL cells revealed that up-regulation of HSPA1A encoding Hsp70, and genes related to cell cycle arrest (i.e. CDKN1A). Genes regulating cell proliferation or anti-apoptosis (i.e. MYC, BCL2 and Cyclin C), genes related to cytokine or chemokine (i.e. IL9, CCL 17, and CCL27), and notably, genes involved in Wnt/-catenin signaling pathway (i.e.TCF7L2 and TCF4), were remarkably repressed. Inhibition of AKT at the protein level was also evident, suggesting the possibility that AKT may down-regulates -catenin/ TCF7L2 pathways in response to Hsp90 inhibitors in ATL cells. Conclusion. Our results have provided new insights into the complex molecular pharmacology of Hsp90 inhibitors, and suggest that Hsp90 inhibitors might be beneficial as anti-proliferative agent in treating ATL patients. Six samples treated with Hsp90 inhibitors (17-AAG or 17-DMAG) were analyzed in biological duplicate.

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Molecular targets of bortezomib on adult T-cell leukemia cells

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