HSF1 promotes the repopulation of post-senescent fatty hepatocellular carcinoma cell via modulating HSP90α/P53 complex stability.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE261886 | GEO | 2025/03/01
REPOSITORIES: GEO
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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
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 | GSE85732 | GEO
Project description:BCR-ABL1+ leukemia entity still is associated with poor prognosis and new therapies are urgently needed. Heat shock proteins of 90 kDa (HSP90) have been widely studied due to their chaperone function, implicated in stabilizing various oncoproteins, including BCR-ABL1 kinase. However, HSP90 inhibitors (HSP90i) have not entered routinely in clinics, primarily due to the associated resistance via heat shock response (HSR) induction and dose limiting toxicity. Accordingly to study complications coupled with HSP90i, with aim to develop a novel strategy for therapy-refractory BCR-ABL1+ leukemia, genetic knockout (KO) models of cytosolic HSP90α/β isoforms were generated. Notably, β-KO cells displayed augmented HSR, whereas, α-KO cells revealed higher abundance of BCR-ABL1-foci and related hyperactive downstream pro-survival signaling. Although there is a strong compensatory behavior reported among HSP90α and β isoforms in their chaperoning their client proteins, global multi-omics profiling of α- vs. β-KO cells revealed a distinctive phenotype of the regulated signaling networks. Whereas in vivo engraftment of BCR-ABL1+ cells was found significantly reduced upon α-KO, validated by the prolonged overall survival of the mice. Later to investigate the acquired resistance evoked upon pharmacological targeting of HSP90, resistant cells were generated by chronic exposure of distinct HSP90i. Strikingly, clinically advanced (HSP90i) PU-H71-resistant cells acquired amplification and a distinctive mutation (S164F) in the HSP90AA1 locus, with concomitant elevation of HSP90α and ALDH1A1 expression, via activating ribosomal protein S6 kinase. Moreover BCR-ABL1+ cells displayed hypersensitivity toward CDK7i upon α-KO or when applied in combination with HSP90i, noticeably due to elevated CDK7 and androgen receptor (AR) signaling.
2022-07-19 | GSE208005 | GEO
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
Project description:Tumor cells modulate host immunity by secreting extracellular vesicles (EV) and soluble factors in circulation. Their interactions with myeloid cells could lead to the generation of myeloid-derived suppressor cells (MDSC), which strongly inhibit the anti-tumor function of T and NK cells. We demonstrated previously that EV derived from mouse and human melanoma cells induced such immunosuppressive activity via upregulating the expression of programmed cell death ligand 1 (PD-L1) on myeloid cells that was dependent on the heat-shock protein 90a (HSP90a) in EV and on the toll-like receptor (TLR) on myeloid cells. Here, we investigated whether soluble HSP90α could convert monocytes into immunosuppressive MDSC. CD14+ monocytes were isolated from the peripheral blood of healthy donors, incubated with human rHSP90α alone or in the presence of inhibitors of TLR4 signaling and analyzed by flow cytometry. Inhibition of T cell proliferation assay was applied to assess immunosuppressive function of rHSP90α-treated monocytes. The concentration of HSP90α was measured by ELISA in plasma of advanced melanoma patients and correlated with clinical outcome. We found that the incubation of monocytes with rHSP90α for 16 h resulted in a strong upregulation of PD-L1 expression, whereas ROS and NO production as well as the expression of arginase-1, adenosine producing ectoenzymes CD39 and CD73 remained unchanged. The PD-L1 upregulation can be blocked by anti-TLR4 antibodies and an NF-κB inhibitor. After longer incubation (for 24h), rHSP90α-treated monocytes downregulated HLA-DR expression and acquired an augmented viability and resistance to apoptosis. Moreover, these monocytes were converted into MDSC indicated by their capacity to inhibit T cell proliferation mediated by TLR4 signaling as well as PD-L1 and indolamin-2,3-Dioxygenase (IDO) 1 expression. Higher levels of HSP90α in plasma of melanoma patients correlated with augmented PD-L1 expression on circulating monocytic (M) MDSC. Furthermore, melanoma patients with high levels of HSP90α displayed shorter progression-free survival (PSF) upon the treatment with immune checkpoint inhibitors (ICI).
2022-06-29 | GSE207075 | GEO
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
Project description:HSP90, found in all kingdoms of life, is a major chaperone protein regulating many client proteins. We demonstrated that HSP90α, one of two paralogs duplicated in vertebrates, plays an important role in the biogenesis of fetal PIWI-interacting RNAs (piRNA), which act against the transposon activities, in mouse male germ cells. The knockout mutation of Hsp90α resulted in a large reduction in the expression of primary and secondary piRNAs and mislocalization of MIWI2, a PIWI homolog. Whereas the mutation in Fkbp6 encoding a co-chaperone reduced piRNAs of 28-32 nucleotides in length, the Hsp90α mutation reduced piRNAs of 24-32 nucleotides, suggesting the presence of both FKBP6-dependent and -independent actions of HSP90α. Although DNA methylation and mRNA levels of L1 retrotransposon were largely unchanged in the Hsp90α mutant testes, the L1-encoded protein was increased, suggesting the presence of post-transcriptional regulation. This study revealed the specialized function of the HSP90α isofom in the piRNA biogenesis and repression of retrotransposons during the development of male germ cells in mammals. Total RNA was extracted from WT and Hsp90α KO testes at E16.5 (20 testes for each), and used for making a small RNA library with TruSeq Small RNA Library Preparation Kit (Illumina). The libraries were sequenced on MiSeq (Illumina) by 50-bp single-end sequencing.
2014-09-30 | E-GEOD-54515 | biostudies-arrayexpress
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.
2013-01-10 | GSE38972 | GEO
Project description:Microglial overactivation is actively involved in the pathogenesis of neurodegenerative diseases. Polo-like kinase 2 (PLK2) is a serine/threonine protein kinase associated with the regulation of synaptic plasticity and centriole duplication. Here, we identified PLK2 as an important early response gene in lipopolysaccharide (LPS)-stimulated microglial cells. Knockdown or inhibition of PLK2 remarkably attenuated LPS-induced expression of pro-inflammatory factors such as IL-1β, IL-6, COX2, TNF-α, and iNOS in microglial cells via suppressing the IKKβ-NF-κB signaling pathway. Notably, overexpression of PLK2 induced expression of pro-inflammatory factors and NF-κB transcriptional activation in the absence of inflammatory stimuli. Mechanistically, co-immunoprecipitation experiments revealed association between PLK2 and IKKβ, whereas GST pull-down assay showed no direct interaction between PLK2 and IKKβ. Proteomic analysis and in vitro kinase assay identified heat shock protein 90 alpha (HSP90α), a regulator of IKKβ activity, as a novel PLK2 substrate. Knockdown or pharmacological inhibition of HSP90α abolished PLK2-mediated activation of NF-κB transcriptional activity and microglial inflammatory activation. Furthermore, phosphoproteomic analysis pinpointed Ser252 and Ser263 on HSP90α as novel phosphorylation targets of PLK2. Subsequent functional studies demonstrated that re-expression of phosphor-dead mutation of these two phosphorylation sites on HSP90α failed to rescue the PLK2-induced activation of the NF-κB signaling. Lastly, conditional knockout of PLK2 in microglial cells dramatically ameliorated neuroinflammation and subsequent dopaminergic neuron loss in an intracranial LPS-induced mouse PD model. The present study revealed, for the first time, that PLK2 promoted microglial activation through the phosphorylation of HSP90α and subsequent activation of the IKKβ-NF-κB signaling pathway. Consequently, PLK2 emerges as a potential therapeutic target for the amelioration of neuroinflammation-related diseases.
2024-09-04 | GSE272635 | GEO
Project description:Microglial overactivation is actively involved in the pathogenesis of neurodegenerative diseases. Polo-like kinase 2 (PLK2) is a serine/threonine protein kinase associated with the regulation of synaptic plasticity and centriole duplication. Here, we identified PLK2 as an important early response gene in lipopolysaccharide (LPS)-stimulated microglial cells. Knockdown or inhibition of PLK2 remarkably attenuated LPS-induced expression of pro-inflammatory factors such as IL-1β, IL-6, COX2, TNF-α,and iNOS in microglial cells via suppressing the IKKβ-NF-κB signaling pathway.Notably, overexpression of PLK2 induced expression of pro-inflammatory factors and NF-κB transcriptional activation in the absence of inflammatory stimuli. Mechanistically,co-immunoprecipitation experiments revealed association between PLK2 and IKKβ, whereas GST pull-down assay showed no direct interaction between PLK2 and IKKβ. Proteomic analysis and in vitro kinase assay identified heat shock protein 90 alpha (HSP90α), a regulator of IKKβ activity, as a novel PLK2 substrate. Knockdown or pharmacological inhibition of HSP90α abolished PLK2-mediated activation of NF-κB transcriptional activity and microglial inflammatory activation. Furthermore,phosphoproteomic analysis pinpointed Ser252 and Ser263 on HSP90α as novel phosphorylation targets of PLK2. Subsequent functional studies demonstrated that re-expression of phosphor-dead mutation of these two phosphorylation sites on HSP90α failed to rescue the PLK2-induced activation of the NF-κB signaling. Lastly, conditional knockout of PLK2 in microglial cells dramatically ameliorated neuroinflammation and subsequent dopaminergic neuron loss in an intracranial LPS-induced mouse PD model. The present study revealed, for the first time, that PLK2 promoted microglial activation through the phosphorylation of HSP90α and subsequent activation of the IKKβ-NF-κB signaling pathway. Consequently, PLK2 emerges as a potential therapeutic target for the amelioration of neuroinflammation-related diseases.
2024-09-04 | GSE276245 | GEO