Prostate cancer and the unfolded protein response

Storm, Margrethe Larsdatter; Sheng, Xia; Arnoldussen, Yke Jildouw; Saatcioglu, Fahri

doi:10.18632/oncotarget.9912

Cited by 64 publications

(65 citation statements)

References 150 publications

(153 reference statements)

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“…In prostate cancer, the research of UPR was limited and unclear. Storm et al indicated that UPR activation was negatively associated with PCa progression [20]. In present study, we found the expression of these proteins was not only increased in prostate cancer, but also associated with Gleason scores, PSA concentration and so on.…”

Section: Discussionsupporting

confidence: 62%

Activation of UPR Signaling Pathway is Associated With the Malignant Progression and Poor Prognosis in Prostate Cancer

Liu

Xiao

et al. 2016

The Prostate

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Section: Discussionsupporting

confidence: 62%

Activation of UPR Signaling Pathway is Associated With the Malignant Progression and Poor Prognosis in Prostate Cancer

Liu

Xiao

et al. 2016

The Prostate

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“…Prostate, as a mainly secretory organ, is especially dependent on proper function of endoplasmic reticulum (ER) and ER‐associated degradation (ERAD). ERAD malfunction or insufficiency leads to ER stress and activation of the unfolded protein response (UPR) . Several factors of ERAD machinery are upregulated in PCa, and UPR activation in PCa has been recently demonstrated, providing a possible vulnerability exploitable therapeutically .…”

Section: Resultsmentioning

confidence: 99%

“…Immunofluorescence analysis confirmed a robust HSR manifested by formation of HSF1 nuclear stress foci 27 (Figures 4C and 4D) and increase of heat shock protein 70 (HSP70), the main HSR effector, in all tested cell lines ( Figure 4E). The PCa cells also strongly activate UPR manifested by elevated ATF4, CHOP, and phospho-eIF2α, established UPR markers 22 (Figures 5A and 5B). cancer.…”

Section: Disulfiram As a Candidate Drug For Pca Treatmentmentioning

confidence: 91%

“…ERAD malfunction or insufficiency leads to ER stress and activation of the unfolded protein response (UPR). 22 Several factors of ERAD machinery are upregulated in PCa, 23 and UPR activation in PCa has been recently demonstrated, providing a possible vulnerability exploitable therapeutically. 24 We have recently shown that DSF targets cancer via inhibition of the p97/NPL4 pathway, essential for ERAD.…”

Section: Disulfiram As a Candidate Drug For Pca Treatmentmentioning

confidence: 99%

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Targeting genotoxic and proteotoxic stress‐response pathways in human prostate cancer by clinically available PARP inhibitors, vorinostat and disulfiram

et al. 2018

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Background Castration‐resistant prostate cancer (PCa) represents a serious health challenge. Based on mechanistically‐supported rationale we explored new therapeutic options based on clinically available drugs with anticancer effects, including inhibitors of PARP1 enzyme (PARPi), and histone deacetylases (vorinostat), respectively, and disulfiram (DSF, known as alcohol‐abuse drug Antabuse) and its copper‐chelating metabolite CuET that inhibit protein turnover. Methods Drugs and their combination with ionizing radiation (IR) were tested in various cytotoxicity assays in three human PCa cell lines including radio‐resistant stem‐cell like derived cells. Mechanistically, DNA damage repair, heat shock and unfolded protein response (UPR) pathways were assessed by immunofluorescence and immunoblotting. Results We observed enhanced sensitivity to PARPi/IR in PC3 cells consistent with lower homologous recombination (HR) repair. Vorinostat sensitized DU145 cells to PARPi/IR and decreased mutant p53. Vorinostat also impaired HR‐mediated DNA repair, as determined by Rad51 foci formation and downregulation of TOPBP1 protein, and overcame radio‐resistance of stem‐cell like DU145‐derived cells. All PCa models responded well to CuET or DSF combined with copper. We demonstrated that DSF interacts with copper in the culture media and forms adequate levels of CuET indicating that DSF/copper and CuET may be considered as comparable treatments. Both DSF/copper and CuET evoked hallmarks of UPR in PCa cells, documented by upregulation of ATF4, CHOP and phospho‐eIF2α, with ensuing heat shock response encompassing activation of HSF1 and HSP70. Further enhancing the cytotoxicity of CuET, combination with an inhibitor of the anti‐apoptotic protein survivin (YM155, currently undergoing clinical trials) promoted the UPR‐induced toxicity, yielding synergistic effects of CuET and YM155. Conclusions We propose that targeting genotoxic and proteotoxic stress responses by combinations of available drugs could inspire innovative strategies to treat castration‐resistant PCa.

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“…Localised disease is mostly treated with surgery or radiotherapy. As PCa develops and treatment resistance emerges, the unfolded protein response (UPR) arises as an important adaptive biology co-amplifying with key cancer drivers [1]. The UPR can be cytoprotective but when acutely activated can lead to cell death.…”

mentioning

confidence: 99%

Modulating the unfolded protein response: Impacts of radiation on the response of prostate cancer cells to ONC201

Amoroso

Glass

Liberal

et al. 2019

Preprint

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Running Title: ONC201 can increase radiation response in prostate cancer. AbstractProstate cancer (PCa) is the most common non-cutaneous cancer in men and a notable cause of cancer mortality when it metastasises. Localised disease is mostly treated with surgery or radiotherapy. As PCa develops and treatment resistance emerges, the unfolded protein response (UPR) arises as an important adaptive biology co-amplifying with key cancer drivers [1]. The UPR can be cytoprotective but when acutely activated can lead to cell death. In this study we sought to enhance the acute activation of the UPR using radiation and ONC201, previously reported to be an UPR activator [2]. We found that treating PCa cells with ONC201 quickly increases the expression of components in all arms of the UPR -ATF4, ATF6 and IRE1-XBP1 -culminating in the subsequent cell death. During this time window between UPR activation and cell death we tested the priming effect of short-term administration of ONC201 on radiation responses. Pre-treatment with ONC201 for 24 hours prior to irradiation led to enhanced cytotoxicity compared to radiation alone assessed by cell viability and clonogenic assays. With priming, RNA-Seq analysis showed a sustained suppression of transcripts encoding cell cycle regulators as well as components of the DNA damage response pathways.Phenotypically this was reflected in enhanced cell cycle arrest and induction of necrosis and apoptosis. Furthermore, we demonstrated that short-term administration of inhibitors of cell cycle regulators (Dinaciclib and BI2536), could replicate this priming effect. Thus, we propose future studies to assess the impact of the short-term administration of drugs targeting the UPR and cell cycle regulation to enhance radiotherapy response.

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Prostate cancer and the unfolded protein response

Cited by 64 publications

References 150 publications

Activation of UPR Signaling Pathway is Associated With the Malignant Progression and Poor Prognosis in Prostate Cancer

Activation of UPR Signaling Pathway is Associated With the Malignant Progression and Poor Prognosis in Prostate Cancer

Targeting genotoxic and proteotoxic stress‐response pathways in human prostate cancer by clinically available PARP inhibitors, vorinostat and disulfiram

Modulating the unfolded protein response: Impacts of radiation on the response of prostate cancer cells to ONC201

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