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Wee1 Inhibition sensitizes prostate cancer cells to Hsp90 inhibitor to activate the intrinsic apoptotic pathway

ABSTRACT: Heat shock protein 90 (Hsp90) is an essential evolutionarily conserved molecular chaperone in eukaryotes. Cancer cells rely on Hsp90 to chaperone activated oncoproteins, and its involvement in numerous signaling pathways makes it an attractive target for drug development. Surprisingly, however, the impact of Hsp90 inhibitors on cancer cells is most commonly cytostatic, and efforts to enhance the anti-tumor activity of Hsp90 inhibitors in the clinic remain a significant challenge. In this study, we show that dual inhibition of Wee1 tyrosine kinase and Hsp90 causes prostate cancer cells to undergo apoptosis. Gene-expression profiling revealed that induction of the intrinsic apoptotic pathway by this drug combination coincided with transcriptional down-regulation of Survivin and Wee1, an outcome not seen in cells treated separately with either agent. At the translational level, expression of these two proteins as well as activated Akt was completely abrogated. Similar results were obtained in prostate cancer xenografts. These data establish a novel therapeutic strategy to enhance the efficacy of Hsp90 inhibitors in prostate cancer, and they provide a mechanistic rationale for stimulating the pro-apoptotic activity of Hsp90 inhibitors. In order to explore the mechanism underlying the enhanced cell death caused by Wee1 inhibitorII and 17-AAG combination, we performed microarray analysis using PC3 cells treated with Wee1 inhibitorII alone, 17-AAG alone, or the two drugs in combination.

ORGANISM(S): Homo sapiens

PROVIDER: GSE38972 | GEO | 2013/01/10

SECONDARY ACCESSION(S): PRJNA169502

REPOSITORIES: GEO

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Wee1 Inhibition sensitizes prostate cancer cells to Hsp90 inhibitor to activate the intrinsic apoptotic pathway

Project description:Heat shock protein 90 (Hsp90) is an essential evolutionarily conserved molecular chaperone in eukaryotes. Cancer cells rely on Hsp90 to chaperone activated oncoproteins, and its involvement in numerous signaling pathways makes it an attractive target for drug development. Surprisingly, however, the impact of Hsp90 inhibitors on cancer cells is most commonly cytostatic, and efforts to enhance the anti-tumor activity of Hsp90 inhibitors in the clinic remain a significant challenge. In this study, we show that dual inhibition of Wee1 tyrosine kinase and Hsp90 causes prostate cancer cells to undergo apoptosis. Gene-expression profiling revealed that induction of the intrinsic apoptotic pathway by this drug combination coincided with transcriptional down-regulation of Survivin and Wee1, an outcome not seen in cells treated separately with either agent. At the translational level, expression of these two proteins as well as activated Akt was completely abrogated. Similar results were obtained in prostate cancer xenografts. These data establish a novel therapeutic strategy to enhance the efficacy of Hsp90 inhibitors in prostate cancer, and they provide a mechanistic rationale for stimulating the pro-apoptotic activity of Hsp90 inhibitors. In order to explore the mechanism underlying the enhanced cell death caused by Wee1 inhibitorII and 17-AAG combination, we performed microarray analysis using PC3 cells treated with Wee1 inhibitorII alone, 17-AAG alone, or the two drugs in combination. There are 12 samples in total. There are three experimental replicate. Samples 1, 5 and 9 are control (C) (untreated PC3- prostate cancer cells). Samples 2, 6, and 10 are cells treated with Wee1 inhibitor II (W). Samples 3, 7, and 11 are treated with 17-AAG (A), (an Hsp90 inhibitor). Samples 4, 8, and 12 are treated with both Wee1 inhibitorII and 17-AAG (WA). Samples 5 was removed from our analysis due to weak signal.

2013-01-10 | E-GEOD-38972 | biostudies-arrayexpress

Expression data from human colonic cancer cell line SW480 and its acquired 17-AAG resistance cell line SW480-R

Project description:Heat shock protein 90 (HSP90) is a molecular chaperone required for the stability and function of many proteins. The chaperoning of oncoproteins by HSP90 enhances survival, growth and invasive potential of cancer cells. HSP90 inhibitors are promising new anticancer agents, in which the benzoquinone ansamycin 17-allylamino-17-demethoxygeldanamycin (17-AAG) is currently in clinical evaluation. However, the implications of acquired resistance to this class of drug remain largely unexplored. In the present study, we have generated isogenic human colonic cancer cell line SW480 that is resistant to 17-AAG by continued culturing in the compound. We used microarrays to detail the global programme of gene expression underlying the acquired resistance to 17-AAG in SW480 and SW480-R cell lines.

2015-03-14 | GSE66867 | GEO

Combinatorial targeting of the AR for treatment of prostate cancer.

Project description:Combining different clinical agents to target multiple pathways in prostate cancer cells, including androgen receptor (AR) signaling, is potentially an effective strategy to improve outcomes for men with metastatic disease. We have previously demonstrated that sub-effective concentrations of an AR antagonist, bicalutamide, a histone deacetylase inhibitor, vorinostat (SAHA), and a hsp90 inhibitor, 17-AAG, act synergistically when combined to cause death of AR-dependent prostate cancer cells. In this study, expression profiling of human prostate cancer cells treated with bicalutamide, vorinostat (SAHA) or 17-AAG, alone or in paired combination, was employed to determine the molecular mechanisms underlying these synergistic interactions. We used microarray analysis to determine the global molecular profile contributing to the synergistic cell death in LNCaP human prostate cancer cells caused by combinations of bicalutamide, vorinostat (SAHA), or 17-AAG. LNCaP human prostate cancer cells were treated for 6 hours with drug treatments as follows: vehicle control, 5 uM bicalutamide, 1 uM vorinostat (SAHA), 40 nM 17-AAG, 5 uM bicalutamide + 40 nM 17-AAG, 40 nM 17-AAG + 1 uM vorinostat (SAHA), or 5 uM bicalutamide + 1 uM vorinostat (SAHA). Each treatment was performed in sextuplicate.

2014-03-27 | E-GEOD-56188 | biostudies-arrayexpress

Combinatorial targeting of the AR for treatment of prostate cancer.

2014-03-27 | GSE56188 | GEO

Prospective identification of resistance mechanisms to HSP90 inhibition in KRAS mutant cancer cells [GenomeWideSNP_6]

Project description:Inhibition of the HSP90 chaperone results in depletion of many signaling proteins that drive tumorigenesis, such as downstream effectors of KRAS, the most commonly mutated human oncogene. As a consequence, several small-molecule HSP90 inhibitors are being evaluated in clinical trials as anticancer agents. To prospectively identify mechanisms through which HSP90-dependent cancer cells evade pharmacologic HSP90 blockade, we generated multiple mutant KRAS-driven cancer cell lines with acquired resistance to the purine-scaffold HSP90 inhibitor PU-H71. All cell lines retained dependence on HSP90 function, as evidenced by sensitivity to short hairpin RNA-mediated suppression of HSP90AA1 or HSP90AB1 (also called HSP90α and HSP90β, respectively), and exhibited two types of genomic alterations that interfere with the effects of PU-H71 on cell viability and proliferation: (i) a Y142N missense mutation in the ATP-binding domain of HSP90α that co-occurred with amplification of the HSP90AA1 locus, (ii) genomic amplification and overexpression of the ABCB1 gene encoding the MDR1 drug efflux pump. In support of a functional role for these alterations, exogenous expression of HSP90α Y142N conferred PU-H71 resistance to HSP90-dependent cells, and pharmacologic MDR1 inhibition with tariquidar or lowering ABCB1 expression restored sensitivity to PU-H71 in ABCB1-amplified cells. Finally, comparison with structurally distinct HSP90 inhibitors currently in clinical development revealed that PU-H71 resistance could be overcome, in part, by ganetespib (also known as STA9090) but not tanespimycin (also known as 17-AAG). Together, these data identify potential mechanisms of acquired resistance to small molecules targeting HSP90 that may warrant proactive screening for additional HSP90 inhibitors or rational combination therapies.

2016-12-31 | GSE85733 | GEO

Prospective identification of resistance mechanisms to HSP90 inhibition in KRAS mutant cancer cells [HG-U133_Plus_2]

2016-12-31 | GSE85732 | GEO

Homo sapiens

Project description:Wee1 Inhibition sensitizes prostate cancer cells to Hsp90 inhibitor to activate the intrinsic apoptotic pathway

| PRJNA169502 | ENA

Transcription profiling of human adult T cell leukemia cell lines to investigate the biological pathways of Hsp90 inhibitors

Project description: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), 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. 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-E10) were incubated, with or without Hsp90 inhibitors. Experiment Overall Design: Three ATL cell lines(TaY-E10, MT-2, and MT-4) were cultured in the presence or absence of Hsp90 inhibitors(17-AAG and 17-DMAG).

2009-06-08 | E-GEOD-12287 | biostudies-arrayexpress

Native SEC-MS of the human HT29 colon adenocarcinoma cell line treated with the HSP90 inhibitor tanespimycin (17-AAG)

Project description:The molecular chaperone heat shock protein 90 (HSP90) works in concert with its co-chaperones to stabilize its client proteins, which include several drivers of oncogenesis and malignant progression. Pharmacologic inhibitors of HSP90 are proposed to trigger widespread remodeling of cellular protein complexes, including dissociation of co-chaperones from HSP90, disruption of client protein signaling networks, and recruitment of the protein ubiquitination and degradation machinery. However, proteomic studies to date have focused on inhibitor-induced changes in total protein levels, often overlooking protein complex alterations. Here, we use size-exclusion chromatography in combination with mass spectrometry (SEC-MS) to characterize the changes in native protein complexes following treatment with the HSP90 inhibitor 17-AAG in the human HT29 colon adenocarcinoma cell line.

2022-12-20 | PXD033459 | Pride

Drug combination of 17-AAG and Belinostat on MDA-MB-231 breast cancer cells

Project description:Breast cancer is the most common cancer that threatens women's health. While the strategy of drug combination can help to reduce adverse effects and to overcome the resistance of clinical treatment of single drug. In this work, we report the synergetic effect between a HSP90 inhibitor 17-AAG and a HDAC inhibitor Belinostat, on the triple-negative breast cancer MDA-MB-231 cells. The RNA-Seq data analysis showed that the most over-represented KEGG pathways in the combination group came from migration or invasion related genes, which were not observed in the differentially expressed genes after the treatment of 17-AAG or Belinostat alone.

2019-05-17 | GSE129944 | GEO

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