snx-2112 and Urinary-Bladder-Neoplasms

The 90 kD heat shock proteins (Hsp90) are molecular chaperones that are responsible for the folding of select proteins, many of which are directly associated with cancer progression. Consequently, inhibition of the Hsp90 protein folding machinery results in a combinatorial attack on numerous oncogenic pathways. Seventeen small-molecule inhibitors of Hsp90 have entered clinical trials for the treatment of cancer, all of which bind the Hsp90 N-terminus and exhibit

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Gene Silencing; Heterocyclic Compounds, 4 or More Rings; HSP90 Heat-Shock Proteins; Humans; Models, Molecular; Molecular Conformation; Neoplasms; Protein Folding; Small Molecule Libraries; Structure-Activity Relationship; Substrate Specificity; Urinary Bladder Neoplasms

Heat shock protein 90 (HSP90) inhibition is an attractive strategy for cancer treatment. Several HSP90 inhibitors have shown promising effects in clinical oncology trials. However, little is known about HSP90 inhibition-mediated bladder cancer therapy. Here, we report a quantitative proteomic study that evaluates alterations in protein expression and histone post-translational modifications (PTMs) in bladder carcinoma in response to HSP90 inhibition. We show that 5 HSP90 inhibitors (AUY922, ganetespib, SNX2112, AT13387, and CUDC305) potently inhibited the proliferation of bladder cancer 5637 cells in a dose- and time-dependent manner. Our proteomic study quantified 518 twofold up-regulated and 811 twofold down-regulated proteins common to both AUY922 and ganetespib treatment. Bioinformatic analyses revealed that those differentially expressed proteins were involved in multiple cellular processes and enzyme-regulated signaling pathways, including chromatin modifications and cell death-associated pathways. Furthermore, quantitative proteome studies identified 14 types of PTMs with 93 marks on the core histones, including 34 novel histone marks of butyrylation, citrullination, 2-hydroxyisobutyrylation, methylation, O-GlcNAcylation, propionylation, and succinylation in AUY922- and ganetespib-treated 5637 cells. Together, this study outlines the association between proteomic changes and histone PTMs in response to HSP90 inhibitor treatment in bladder carcinoma cells, and thus intensifies the understanding of HSP90 inhibition-mediated bladder cancer therapeutics.

Topics: Antineoplastic Agents; Benzamides; Benzodioxoles; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Gene Expression Regulation, Neoplastic; Heterocyclic Compounds, 4 or More Rings; Histones; HSP90 Heat-Shock Proteins; Humans; Imidazoles; Isoindoles; Isoxazoles; Protein Processing, Post-Translational; Proteomics; Resorcinols; Triazoles; Urinary Bladder Neoplasms