scholarly journals Heat shock protein 90 is involved in the regulation of HMGA2-driven growth and epithelial-to-mesenchymal transition of colorectal cancer cells

PeerJ ◽  
2016 ◽  
Vol 4 ◽  
pp. e1683 ◽  
Author(s):  
Chun-Yu Kao ◽  
Pei-Ming Yang ◽  
Ming-Heng Wu ◽  
Chi-Chen Huang ◽  
Yi-Chao Lee ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Protein Expression ◽  
Cancer Cells ◽  
Heat Shock Protein 90 ◽  
Hsp90 Inhibitors ◽  
Hsp90 Inhibition ◽  
Mesenchymal Transition ◽  
Hmga2 Protein

High Mobility Group AT-hook 2 (HMGA2) is a nonhistone chromatin-binding protein which acts as a transcriptional regulating factor involved in gene transcription. In particular, overexpression of HMGA2 has been demonstrated to associate with neoplastic transformation and tumor progression in Colorectal Cancer (CRC). Thus, HMGA2 is a potential therapeutic target in cancer therapy. Heat Shock Protein 90 (Hsp90) is a chaperone protein required for the stability and function for a number of proteins that promote the growth, mobility, and survival of cancer cells. Moreover, it has shown strong positive connections were observed between Hsp90 inhibitors and CRC, which indicated their potential for use in CRC treatment by using combination of data mining and experimental designs. However, little is known about the effect of Hsp90 inhibition on HMGA2 protein expression in CRC. In this study, we tested the hypothesis that Hsp90 may regulate HMGA2 expression and investigated the relationship between Hsp90 and HMGA2 signaling. The use of the second-generation Hsp90 inhibitor, NVP-AUY922, considerably knocked down HMGA2 expression, and the effects of Hsp90 and HMGA2 knockdown were similar. In addition, Hsp90 knockdown abrogates colocalization of Hsp90 and HMGA2 in CRC cells. Moreover, the suppression of HMGA2 protein expression in response to NVP-AUY922 treatment resulted in ubiquitination and subsequent proteasome-dependant degradation of HMGA2. Furthermore, RNAi-mediated silencing of HMGA2 reduced the survival of CRC cells and increased the sensitivity of these cells to chemotherapy. Finally, we found that the NVP-AUY922-dependent mitigation of HMGA2 signaling occurred also through indirect reactivation of the tumor suppressor microRNA (miRNA), let-7a, or the inhibition of ERK-regulated HMGA2 involved in regulating the growth of CRC cells. Collectively, our studies identify the crucial role for the Hsp90-HMGA2 interaction in maintaining CRC cell survival and migration. These findings have significant implications for inhibition HMGA2-dependent tumorigenesis by clinically available Hsp90 inhibitors.

Proteomic analysis of proteome and histone post-translational modifications in heat shock protein 90 inhibition-mediated bladder cancer therapeutics.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e16030-e16030
Author(s):  
Qingdi Quentin Li ◽  
Thomas Sanford ◽  
Spencer Krane ◽  
Kai Hans Hammerich ◽  
Jane B Trepel ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Cancer Cells ◽  
Heat Shock Protein 90 ◽  
Hsp90 Inhibitors ◽  
Hsp90 Inhibition ◽  
Post Translational Modifications ◽  
Bladder Cancer Cells ◽  
Proteomic Study

e16030 Background: Heat shock protein 90 (HSP90) is a chaperone for many proteins integral development of cancer, making inhibition of HSP90 an attractive strategy for cancer treatment. However, little is known about HSP90 inhibition-mediated bladder cancer therapy. Here, we present a quantitative proteomic study that evaluates alterations in protein expression and histone post-translational modifications (PTMs) in bladder cancer in response to HSP90 inhibition. Methods: We assessed the antitumor activity of five HSP90 inhibitors in 5637 bladder cancer cell line using MTS, cell viability, and caspase 3/7 assays. We then performed a proteomic analysis of cells before and after treatment with the HSP90 inhibitors and assessed for changes. Results: We show that the five HSP90 inhibitors (AUY922, ganetespib, SNX2112, AT13387, and CUDC305) potently inhibited the proliferation of bladder cancer 5637 cells. HSP90 inhibitors also had differential effects on cell survival between bladder cancer cells and uroepithelial cells. Our proteomic study quantified 518 twofold up-regulated and 811 twofold downregulated proteins common to both AUY922 and ganetespib treatment (P < 0.05). The subsequent bioinformatic analysis revealed that those differentially expressed proteins were involved in chromatin modifications and cell death-associated pathways. Further, quantitative proteome studies identified 14 different types of PTMs with 93 marks on the core histones, including 34 novel histone marks of butyrylation, citrullination, 2-hydroxyisobutyrylation, propionylation, and succinylation in AUY922- and ganetespib-treated 5637 cells, suggesting that HSP90 inhibitors may exert multiple cytotoxic actions in bladder cancer cells by inhibiting HSP90 activity or altering the structure of chromatin. Conclusions: This study outlines the association between proteomic changes and histone PTMs in response to HSP90 inhibitor treatment in bladder cancer cells, and supports the notion that HSP90 inhibitors both as single agents and in combination might provide new therapeutic options for bladder cancer treatment and thus warrant further preclinical exploration.

Heat-shock protein 90 inhibition in autoimmunity to type VII collagen: evidence that nonmalignant plasma cells are not therapeutic targets

Blood ◽  
2011 ◽  
Vol 117 (23) ◽  
pp. 6135-6142 ◽  
Author(s):  
Michael Kasperkiewicz ◽  
Ralf Müller ◽  
Rudolf Manz ◽  
Moritz Magens ◽  
Christoph M. Hammers ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Plasma Cells ◽  
Protein Biosynthesis ◽  
Heat Shock Protein 90 ◽  
Hsp90 Inhibitors ◽  
Hsp90 Inhibition ◽  
Type Vii Collagen

Abstract Blocking heat-shock protein 90 (Hsp90) induces death of malignant plasma cells by activation of the unfolded protein response, a signaling pathway activated by accumulation of misfolded proteins within the endoplasmic reticulum. We hypothesized that nontransformed plasma cells are also hypersensitive to Hsp90 inhibition because of their high amount of protein biosynthesis. To investigate this hypothesis, 2 different Hsp90 inhibitors, the geldanamycin derivative 17-DMAG and the nontoxic peptide derivative TCBL-145, were applied to mice with experimental epidermolysis bullosa acquisita, an autoimmune bullous disease characterized by autoantibodies against type VII collagen of the dermal-epidermal junction. Both inhibitors ameliorated clinical disease of type VII collagen–immunized mice, suppressed auto-antibody production, and reduced dermal neutrophilic infiltrate. Interestingly, total plasma cell numbers, type VII collagen–specific plasma cells, and germinal center B cells were unaffected by anti-Hsp90 treatment in vivo. However, T-cell proliferation was potently inhibited, as evidenced by the reduced response of isolated lymph node cells from immunized mice to in vitro restimulation with anti-CD3/CD28 antibody or autoantigen in the presence of Hsp90 inhibitors. Our results suggest that Hsp90 blockade has no impact on normal or autoreactive plasma cells in vivo and indentify T cells as targets of anti-Hsp90 treatment in autoimmunity to type VII collagen.

scholarly journals Novel Heat Shock Protein 90 Inhibitors Suppress P-Glycoprotein Activity and Overcome Multidrug Resistance in Cancer Cells

2019 ◽  
Vol 20 (18) ◽  
pp. 4575 ◽  
Author(s):  
Jelena Dinić ◽  
Ana Podolski-Renić ◽  
Mirna Jovanović ◽  
Loana Musso ◽  
Ivanka Tsakovska ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Heat Shock ◽  
Cell Growth ◽  
Heat Shock Protein ◽  
Cancer Cells ◽  
Heat Shock Protein 90 ◽  
Dependent Manner ◽  
Hsp90 Inhibitors ◽  
Relationship Analysis ◽  
P Glycoprotein

Heat Shock Protein 90 (Hsp90) chaperone interacts with a broad range of client proteins involved in cancerogenesis and cancer progression. However, Hsp90 inhibitors were unsuccessful as anticancer agents due to their high toxicity, lack of selectivity against cancer cells and extrusion by membrane transporters responsible for multidrug resistance (MDR) such as P-glycoprotein (P-gp). Recognizing the potential of new compounds to inhibit P-gp function and/or expression is essential in the search for effective anticancer drugs. Eleven Hsp90 inhibitors containing an isoxazolonaphtoquinone core were synthesized and evaluated in two MDR models comprised of sensitive and corresponding resistant cancer cells with P-gp overexpression (human non-small cell lung carcinoma and colorectal adenocarcinoma). We investigated the effect of Hsp90 inhibitors on cell growth inhibition, P-gp activity and P-gp expression. Structure–activity relationship analysis was performed in respect to cell growth and P-gp inhibition. Compounds 5, 7, and 9 directly interacted with P-gp and inhibited its ATPase activity. Their potential P-gp binding site was identified by molecular docking studies. In addition, these compounds downregulated P-gp expression in MDR colorectal carcinoma cells, showed good relative selectivity towards cancer cells, while compound 5 reversed resistance to doxorubicin and paclitaxel in concentration-dependent manner. Therefore, compounds 5, 7 and 9 could be promising candidates for treating cancers with P-gp overexpression.

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