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Mitoribosome sensitivity to HSP70 inhibition uncovers metabolic liabilities of castration-resistant prostate cancer

ABSTRACT: TMT-MS of whole cell lysate collected from 22Rv1 castration-resistant prostate cancer cells treated with 5 µM JG-98 for 4 hours.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Leonard M. Neckers

PROVIDER: PXD038684 | JPOST Repository | Tue Apr 25 00:00:00 BST 2023

REPOSITORIES: jPOST

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			Action	DRS
	P747-VT22-TMT10PLEX-F1.raw	Raw
	P747-VT22-TMT10PLEX-F10.raw	Raw
	P747-VT22-TMT10PLEX-F11.raw	Raw
	P747-VT22-TMT10PLEX-F12.raw	Raw
	P747-VT22-TMT10PLEX-F13.raw	Raw

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Mitoribosome sensitivity to HSP70 inhibition uncovers metabolic liabilities of castration-resistant prostate cancer.

Echtenkamp Frank J FJ Ishida Ryo R Rivera-Marquez Genesis M GM Maisiak Marisa M Johnson Oleta T OT Shrimp Jonathan H JH Sinha Arnav A Ralph Stephen John SJ Nisbet Ian I Cherukuri Murali Krishna MK Gestwicki Jason E JE Neckers Leonard M LM

PNAS nexus 20230403 4

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 alloster ...[more]

PMID: 37091547

Similar Datasets

Mitoribosome sensitivity to HSP70 inhibition uncovers metabolic liabilities of castration-resistant prostate cancer.

Project description: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.

| S-EPMC10118397 | biostudies-literature

Inhibition of growth factor signaling prevents SARS-CoV-2 replication

Project description:Caco-2 cells were mock-infected or infected with SARS-CoV-2 patient isolates (in biological quintruplicates) for one hour, washed, and incubated for 24 hours before cell harvest. Extracted proteins were digested and split to 1) carry out whole-cell proteomics of a tandem mass tag (TMT) 10-plex samples using liquid chromatography synchronous precursor selection mass spectromety (LC-SPS-MS3), or 2) use Fe-NTA phosphopeptide enrichment (achieving 98% enrichment) for phospho proteome analyses of a TMT 10-plex analyzed by LC-MS2 First 5 channels = control Last 5 channels = infected

2020-05-15 | PXD018357 | Pride

MYC-mediated ribosomal gene expression sensitizes enzalutamide-resistant cells to EP300/CREBBP inhibitors

Project description:Various mechanisms have been reported to be responsible for enzalutamide resistance in prostate cancer. In our previous studies, we have demonstrated that the histone acetyltransferase EP300 is highly expressed in castration therapy-resistant prostate cancer. In the present study, we investigated the role of EP300/CREBBP in enzalutamide-resistant prostate cancer. Enzalutamide resistant and control DuCaP cells generatd previously were treated with histone acetyltransferase (C646) and bromodomain (I-CBP112) inhibitors of EP300/CREBBP. Additionally Enzalutamide resistant cells under 5 µM enzalutamide treatment and control LNCaP cells were analyzed. DuCaP and LNCaP cells were seeded in 6-well-plates at 8 x 10^5 and 6 x 10^5 cells per well. The following day, DuCaP cells were treated with 8 µM enzalutamide, 10 µM C646, 10 µM I-CBP112 or DMSO equivalent for 24 hr.

2021-02-17 | GSE163240 | GEO

Methylation data from biological replicates of imatinib and nilotinib resistant K-562 cells

Project description:Resistant cells were generated by stepwise exposure to increasing concentrations of imatinib or nilotinib to establish 0.5 and 2 µM imatinib and 0.1 µM nilotinib resistant cells. This procedure was performed twice independently to establish biological replicates of TKI resistance. We analyzed genome-wide methylation to investigate changes in methylation during the development of TKI resistance.

2022-05-21 | GSE203443 | GEO

Gene expression data from biological replicates of imatinib and nilotinib resistant K-562 cells

Project description:Resistant cells were generated by stepwise exposure to increasing concentrations of imatinib or nilotinib to establish 0.5 and 2 µM imatinib and 0.1 µM nilotinib resistant cells. This procedure was performed twice independently to establish biological replicates of TKI resistance. We performed microarrays to analyze the changes in gene expression during the development of TKI resistance.

2022-05-21 | GSE203442 | GEO

Gene expression data from biological replicates of imatinib and nilotinib resistant K-562 cells.

Project description:Resistant cells were generated by stepwise exposure to increasing concentrations of imatinib or nilotinib to establish 0.5 and 2 µM imatinib and 0.05 µM nilotinib resistant cells. This procedure was performed twice independently to establish biological replicates of TKI resistance. We performed microarrays (Clariom S) to analyze the changes in gene expression during the development of TKI resistance.

2023-06-30 | GSE227347 | GEO

PXD018357-2 Inhibition of growth factor signaling prevents SARS-CoV-2 replication [Reanalysis: PXD018357]

2023-03-25 | RPXD034696 | JPOST Repository

PXD018357-1 Inhibition of growth factor signaling prevents SARS-CoV-2 replication [Reanalysis: PXD018357]

2023-03-25 | RPXD034695 | JPOST Repository

Identification of drivers and therapeutic vulnerabilities in anti-androgen resistant prostate cancer cells

Project description:Inhibition of the androgen receptor (AR) by anti-androgens is the standard treatment for castration resistant prostate cancer (CRPC), but it inevitably leads to the development of resistance. We generated two multi anti-androgen resistant cell-line models by treatment of LNCaP cells with enzalutamide (ResA) and RD-162 (ResB). Both cell-lines have an AR independent, non-neuroendocrine phenotype. To identify the resistance mechanisms we performed RNASeq analysis. To this end, the three cell-lines were plated in medium with 5% dextran-coated charcoal (DCC) treated FCS at a density of 1 million cells/well in 6-well plates. After 24 hours of steroid starvation the cells were treated with 10 nM of the androgen dihydrotestosterone (DHT), 10 µM of the anti-androgen enzalutamide, a combination of the two, or vehicle (DMSO) for 18 hours.

2019-09-26 | GSE130534 | GEO

Inhibition of growth factor signaling prevents SARS-CoV-2 replication

2020-05-28 | MSV000085494 | MassIVE