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  1. Article ; Online: Mitoribosome sensitivity to HSP70 inhibition uncovers metabolic liabilities of castration-resistant prostate cancer.

    Echtenkamp, Frank J / Ishida, Ryo / Rivera-Marquez, Genesis M / Maisiak, Marisa / Johnson, Oleta T / Shrimp, Jonathan H / Sinha, Arnav / Ralph, Stephen John / Nisbet, Ian / Cherukuri, Murali Krishna / Gestwicki, Jason E / Neckers, Leonard M

    PNAS nexus

    2023  Volume 2, Issue 4, Page(s) pgad115

    Abstract: The androgen receptor is a key regulator of prostate cancer and the principal target of current prostate cancer therapies collectively termed androgen deprivation therapies. Insensitivity to these drugs is a hallmark of progression to a terminal disease ... ...

    Abstract The androgen receptor is a key regulator of prostate cancer and the principal target of current prostate cancer therapies collectively termed androgen deprivation therapies. Insensitivity to these drugs is a hallmark of progression to a terminal disease state termed castration-resistant prostate cancer. Therefore, novel therapeutic options that slow progression of castration-resistant prostate cancer and combine effectively with existing agents are in urgent need. We show that JG-98, an allosteric inhibitor of HSP70, re-sensitizes castration-resistant prostate cancer to androgen deprivation drugs by targeting mitochondrial HSP70 (HSPA9) to suppress aerobic respiration. Rather than impacting androgen receptor stability as previously described, JG-98's primary effect is inhibition of mitochondrial translation, leading to disruption of electron transport chain activity. Although functionally distinct from HSPA9 inhibition, direct inhibition of the electron transport chain with a complex I or II inhibitor creates a similar physiological state capable of re-sensitizing castration-resistant prostate cancer to androgen deprivation therapies. These data identify a significant role for HspA9 in mitochondrial ribosome function and highlight an actionable metabolic vulnerability of castration-resistant prostate cancer.
    Language English
    Publishing date 2023-04-03
    Publishing country England
    Document type Journal Article
    ISSN 2752-6542
    ISSN (online) 2752-6542
    DOI 10.1093/pnasnexus/pgad115
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Selective vulnerabilities in the proteostasis network of castration-resistant prostate cancer.

    Shkedi, Arielle / Taylor, Isabelle R / Echtenkamp, Frank / Ramkumar, Poornima / Alshalalfa, Mohamed / Rivera-Márquez, Génesis M / Moses, Michael A / Shao, Hao / Karnes, Robert Jeffrey / Neckers, Len / Feng, Felix / Kampmann, Martin / Gestwicki, Jason E

    Cell chemical biology

    2022  Volume 29, Issue 3, Page(s) 490–501.e4

    Abstract: Castration-resistant prostate cancer (CRPC) is associated with an increased reliance on heat shock protein 70 (HSP70), but it is not clear what other protein homeostasis (proteostasis) factors might be involved. To address this question, we performed ... ...

    Abstract Castration-resistant prostate cancer (CRPC) is associated with an increased reliance on heat shock protein 70 (HSP70), but it is not clear what other protein homeostasis (proteostasis) factors might be involved. To address this question, we performed functional and synthetic lethal screens in four prostate cancer cell lines. These screens confirmed key roles for HSP70, HSP90, and their co-chaperones, but also suggested that the mitochondrial chaperone, HSP60/HSPD1, is selectively required in CRPC cell lines. Knockdown of HSP60 does not impact the stability of androgen receptor (AR) or its variants; rather, it is associated with loss of mitochondrial spare respiratory capacity, partly owing to increased proton leakage. Finally, transcriptional data revealed a correlation between HSP60 levels and poor survival of prostate cancer patients. These findings suggest that re-wiring of the proteostasis network is associated with CRPC, creating selective vulnerabilities that might be targeted to treat the disease.
    MeSH term(s) Cell Line, Tumor ; HSP70 Heat-Shock Proteins/metabolism ; HSP90 Heat-Shock Proteins/genetics ; HSP90 Heat-Shock Proteins/metabolism ; Humans ; Male ; Molecular Chaperones/metabolism ; Prostatic Neoplasms, Castration-Resistant/genetics ; Proteostasis ; Receptors, Androgen/genetics ; Receptors, Androgen/metabolism
    Chemical Substances HSP70 Heat-Shock Proteins ; HSP90 Heat-Shock Proteins ; Molecular Chaperones ; Receptors, Androgen
    Language English
    Publishing date 2022-02-01
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ISSN 2451-9448
    ISSN (online) 2451-9448
    DOI 10.1016/j.chembiol.2022.01.008
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Pharmacologic dissection of the overlapping impact of heat shock protein family members on platelet function.

    Jackson, Joseph W / Rivera-Marquez, Genesis M / Beebe, Kristin / Tran, Andy D / Trepel, Jane B / Gestwicki, Jason E / Blagg, Brian S J / Ohkubo, Shuichi / Neckers, Leonard M

    Journal of thrombosis and haemostasis : JTH

    2020  Volume 18, Issue 5, Page(s) 1197–1209

    Abstract: Background: Platelets play a pivotal role in hemostasis, wound healing, and inflammation, and are thus implicated in a variety of diseases, including cancer. Platelet function is associated with release of granule content, cellular shape change, and ... ...

    Abstract Background: Platelets play a pivotal role in hemostasis, wound healing, and inflammation, and are thus implicated in a variety of diseases, including cancer. Platelet function is associated with release of granule content, cellular shape change, and upregulation of receptors that promote establishment of a thrombus and maintenance of hemostasis.
    Objectives: The role of heat shock proteins (Hsps) in modulating platelet function has been studied for a number of years, but comparative roles of individual Hsps have not been thoroughly examined.
    Methods: We utilized a panel of specific inhibitors of Hsp40, Hsp70, Hsp90, and Grp94 (the endoplasmic reticulum homolog of Hsp90) to assess their impact on several aspects of platelet function.
    Results: Inhibition of each of the aforementioned Hsps reduced alpha granule release. In contrast, there was some selectivity in impacts on dense granule release. Thromboxane synthesis was impaired after exposure to inhibitors of Hsp40, Hsp90, and Grp94, but not after inhibition of Hsp70. Both expression of active glycoprotein IIb/IIIa (GPIIb/IIIa) and fibrinogen-induced platelet shape change were diminished by our inhibitors. In contrast, aggregation was selectively abrogated after inhibition of Hsp40 or Hsp90. Lastly, activated platelet-cancer cell interactions were reduced by inhibition of both Hsp70 and Grp94.
    Conclusions: These data suggest the importance of Hsp networks in regulating platelet activity.
    MeSH term(s) Blood Platelets ; Heat-Shock Proteins/pharmacology ; Hemostasis ; Humans ; Platelet Aggregation ; Platelet Aggregation Inhibitors/pharmacology ; Platelet Glycoprotein GPIIb-IIIa Complex
    Chemical Substances Heat-Shock Proteins ; Platelet Aggregation Inhibitors ; Platelet Glycoprotein GPIIb-IIIa Complex
    Language English
    Publishing date 2020-03-30
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Intramural
    ZDB-ID 2112661-6
    ISSN 1538-7836 ; 1538-7933
    ISSN (online) 1538-7836
    ISSN 1538-7933
    DOI 10.1111/jth.14758
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5805: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)
    Zs.MO 295: Show issues

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  4. Article ; Online: Targeting the Hsp40/Hsp70 Chaperone Axis as a Novel Strategy to Treat Castration-Resistant Prostate Cancer.

    Moses, Michael A / Kim, Yeong Sang / Rivera-Marquez, Genesis M / Oshima, Nobu / Watson, Matthew J / Beebe, Kristin E / Wells, Catherine / Lee, Sunmin / Zuehlke, Abbey D / Shao, Hao / Bingman, William E / Kumar, Vineet / Malhotra, Sanjay V / Weigel, Nancy L / Gestwicki, Jason E / Trepel, Jane B / Neckers, Leonard M

    Cancer research

    2018  Volume 78, Issue 14, Page(s) 4022–4035

    Abstract: Castration-resistant prostate cancer (CRPC) is characterized by reactivation of androgen receptor (AR) signaling, in part by elevated expression of AR splice variants (ARv) including ARv7, a constitutively active, ligand binding domain (LBD)-deficient ... ...

    Abstract Castration-resistant prostate cancer (CRPC) is characterized by reactivation of androgen receptor (AR) signaling, in part by elevated expression of AR splice variants (ARv) including ARv7, a constitutively active, ligand binding domain (LBD)-deficient variant whose expression has been correlated with therapeutic resistance and poor prognosis. In a screen to identify small-molecule dual inhibitors of both androgen-dependent and androgen-independent AR gene signatures, we identified the chalcone C86. Binding studies using purified proteins and CRPC cell lysates revealed C86 to interact with Hsp40. Pull-down studies using biotinylated-C86 found Hsp40 present in a multiprotein complex with full-length (FL-) AR, ARv7, and Hsp70 in CRPC cells. Treatment of CRPC cells with C86 or the allosteric Hsp70 inhibitor JG98 resulted in rapid protein destabilization of both FL-AR and ARv, including ARv7, concomitant with reduced FL-AR- and ARv7-mediated transcriptional activity. The glucocorticoid receptor, whose elevated expression in a subset of CRPC also leads to androgen-independent AR target gene transcription, was also destabilized by inhibition of Hsp40 or Hsp70.
    MeSH term(s) A549 Cells ; Alternative Splicing/drug effects ; Androgen Antagonists/pharmacology ; Androgens/metabolism ; Animals ; Antineoplastic Agents/pharmacology ; COS Cells ; Cell Line ; Cell Line, Tumor ; Cercopithecus aethiops ; HEK293 Cells ; HSP40 Heat-Shock Proteins/metabolism ; HSP70 Heat-Shock Proteins/metabolism ; Humans ; Male ; Mice, Nude ; Molecular Chaperones/metabolism ; Prostatic Neoplasms, Castration-Resistant/drug therapy ; Prostatic Neoplasms, Castration-Resistant/metabolism ; RNA Splicing/drug effects ; Receptors, Androgen/metabolism ; Signal Transduction/drug effects ; Transcription, Genetic/drug effects
    Chemical Substances Androgen Antagonists ; Androgens ; Antineoplastic Agents ; DNAJB1 protein, human ; HSP40 Heat-Shock Proteins ; HSP70 Heat-Shock Proteins ; Molecular Chaperones ; Receptors, Androgen
    Language English
    Publishing date 2018-05-15
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-17-3728
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Uh III Zs.135/5: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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  5. Article ; Online: An Hsp90 co-chaperone protein in yeast is functionally replaced by site-specific posttranslational modification in humans.

    Zuehlke, Abbey D / Reidy, Michael / Lin, Coney / LaPointe, Paul / Alsomairy, Sarah / Lee, D Joshua / Rivera-Marquez, Genesis M / Beebe, Kristin / Prince, Thomas / Lee, Sunmin / Trepel, Jane B / Xu, Wanping / Johnson, Jill / Masison, Daniel / Neckers, Len

    Nature communications

    2017  Volume 8, Page(s) 15328

    Abstract: Heat shock protein 90 (Hsp90) is an essential eukaryotic molecular chaperone. To properly chaperone its clientele, Hsp90 proceeds through an ATP-dependent conformational cycle influenced by posttranslational modifications (PTMs) and assisted by a number ... ...

    Abstract Heat shock protein 90 (Hsp90) is an essential eukaryotic molecular chaperone. To properly chaperone its clientele, Hsp90 proceeds through an ATP-dependent conformational cycle influenced by posttranslational modifications (PTMs) and assisted by a number of co-chaperone proteins. Although Hsp90 conformational changes in solution have been well-studied, regulation of these complex dynamics in cells remains unclear. Phosphorylation of human Hsp90α at the highly conserved tyrosine 627 has previously been reported to reduce client interaction and Aha1 binding. Here we report that these effects are due to a long-range conformational impact inhibiting Hsp90α N-domain dimerization and involving a region of the middle domain/carboxy-terminal domain interface previously suggested to be a substrate binding site. Although Y627 is not phosphorylated in yeast, we demonstrate that the non-conserved yeast co-chaperone, Hch1, similarly affects yeast Hsp90 (Hsp82) conformation and function, raising the possibility that appearance of this PTM in higher eukaryotes represents an evolutionary substitution for HCH1.
    MeSH term(s) Binding Sites ; Chaperonins/metabolism ; Evolution, Molecular ; HEK293 Cells ; HSP90 Heat-Shock Proteins/genetics ; HSP90 Heat-Shock Proteins/metabolism ; Humans ; Molecular Chaperones/genetics ; Molecular Chaperones/metabolism ; Mutation ; Phosphorylation/physiology ; Protein Binding/physiology ; Protein Domains/physiology ; Protein Multimerization/physiology ; Protein Processing, Post-Translational/physiology ; Protein Structure, Secondary/physiology ; Saccharomyces cerevisiae/physiology ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism ; Tyrosine/metabolism
    Chemical Substances AHA1 protein, S cerevisiae ; HCH1 protein, S cerevisiae ; HSP82 protein, S cerevisiae ; HSP90 Heat-Shock Proteins ; Molecular Chaperones ; Saccharomyces cerevisiae Proteins ; Tyrosine (42HK56048U) ; Chaperonins (EC 3.6.1.-)
    Language English
    Publishing date 2017-05-24
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Intramural
    ISSN 2041-1723
    ISSN (online) 2041-1723
    DOI 10.1038/ncomms15328
    Database MEDical Literature Analysis and Retrieval System OnLINE

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