Multiplex profiling identifies clinically relevant signalling proteins in an isogenic prostate cancer model of radioresistance

Inder, S.M.; Bates, Mark; Labhraí, N. Ní; McDermott, Niamh; Schneider, Julia; Erdmann, Gerrit; Jamerson, Taylor A.; Flores, Angela Nilda; Prina-Mello, Adriele; Thirion, P.; Manecksha, Rustom P.; Cormican, David; Finn, Stephen P.; Lynch, Thomas; Marignol, Laure

doi:10.1038/s41598-019-53799-7

Cited by 8 publications

(4 citation statements)

References 62 publications

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“… 10 , 28 In accordance with our data, multiplex protein expression profiling of generated 22Rv1-RR cells revealed that 43 out of the 90 signaling proteins analyzed disclosed significant alterations comparatively to parental cells. 29 Among them, higher p53 protein levels, as well as activation of Notch signaling were observed in RR cells. 29 Altogether, these results emphasize the role of p53 as a driver of radioresistance in PCa.…”

Section: Resultsmentioning

confidence: 96%

“… 29 Among them, higher p53 protein levels, as well as activation of Notch signaling were observed in RR cells. 29 Altogether, these results emphasize the role of p53 as a driver of radioresistance in PCa. Interestingly, Stattin et al reported, in 1996, that p53 immunoreactivity did not significantly correlate with PCa patient disease-specific survival.…”

Section: Resultsmentioning

confidence: 96%

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Epigenetic regulation of TP53 is involved in prostate cancer radioresistance and DNA damage response signaling

Macedo-Silva,

Miranda-Gonçalves,

Tavares

et al. 2023

Sig Transduct Target Ther

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External beam radiotherapy (RT) is a leading first-line therapy for prostate cancer (PCa), and, in recent years, significant advances have been accomplished. However, RT resistance can arise and result in long-term recurrence or disease progression in the worst-case scenario. Thus, making crucial the discovery of new targets for PCa radiosensitization. Herein, we generated a radioresistant PCa cell line, and found p53 to be highly expressed in radioresistant PCa cells, as well as in PCa patients with recurrent/disease progression submitted to RT. Mechanism dissection revealed that RT could promote p53 expression via epigenetic modulation. Specifically, a decrease of H3K27me3 occupancy at TP53 gene promoter, due to increased KDM6B activity, was observed in radioresistant PCa cells. Furthermore, p53 is essential for efficient DNA damage signaling response and cell recovery upon stress induction by prolonged fractionated irradiation. Remarkably, KDM6B inhibition by GSK-J4 significantly decreased p53 expression, consequently attenuating the radioresistant phenotype of PCa cells and hampering in vivo 3D tumor formation. Overall, this work contributes to improve the understanding of p53 as a mediator of signaling transduction in DNA damage repair, as well as the impact of epigenetic targeting for PCa radiosensitization.

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Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 96%

Epigenetic regulation of TP53 is involved in prostate cancer radioresistance and DNA damage response signaling

Macedo-Silva,

Miranda-Gonçalves,

Tavares

et al. 2023

Sig Transduct Target Ther

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“…These features do not allow us to obtain biologically solid results [ 27 , 28 , 29 ]. Recently, several isogenic PCa models of radioresistance were selected after repeated exposure to conventional fractionation of IR [ 30 , 31 ], but no studies have been published so far on PCa resistance to HFRT.…”

Section: Introductionmentioning

confidence: 99%

Radioresistance Mechanisms in Prostate Cancer Cell Lines Surviving Ultra-Hypo-Fractionated EBRT: Implications and Possible Clinical Applications

Sideri

Petragnano

Maggio

et al. 2022

Cancers

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The use of a higher dose per fraction to overcome the high radioresistance of prostate cancer cells has been unsuccessfully proposed. Herein, we present PC3 and DU-145, castration-resistant prostate cancer cell lines that survived a clinically used ultra-higher dose per fraction, namely, radioresistant PC3 and DU-145 cells (PC3RR and DU-145RR). Compared to PC3, PC3RR showed a higher level of aggressive behaviour, with enhanced clonogenic potential, DNA damage repair, migration ability and cancer stem cell features. Furthermore, compared to PC3, PC3RR more efficiently survived further radiation by increasing proliferation and down-regulating pro-apoptotic proteins. No significant changes of the above parameters were described in DU-145RR, suggesting that different prostate cancer cell lines that survive ultra-higher dose per fraction do not display the same grade of aggressive phenotype. Furthermore, both PC3RR and DU-145RR increased antioxidant enzymes and mesenchymal markers. Our data suggest that different molecular mechanisms could be potential targets for future treatments plans based on sequential strategies and synergistic effects of different modalities, possibly in a patient-tailored fashion. Moreover, PC3RR cells displayed an increase in specific markers involved in bone remodeling, indicating that radiotherapy selects a PC3 population capable of migrating to secondary metastatic sites. Finally, PC3RR cells showed a better sensitivity to Docetaxel as compared to native PC3 cells. This suggests that a subset of patients with castration-resistant metastatic disease could benefit from upfront Docetaxel treatment after the failure of radiotherapy.

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“…Furthermore, DigiWest shows a similar sensitivity, reproducibility, and signal linearity as a high-end western blot system [26]. It has been effectively used in the analysis of signaling pathways and for the verification of biomarker candidates [27][28][29][30][31].…”

Section: Introductionmentioning

confidence: 99%

Multiclass cancer classification in fresh frozen and formalin-fixed paraffin-embedded tissue by DigiWest multiplex protein analysis

Bockmayr

Erdmann²,

Treue

et al. 2020

Laboratory Investigation

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Histomorphology and immunohistochemistry are the most common ways of cancer classification in routine cancer diagnostics, but often reach their limits in determining the organ origin in metastasis. These cancers of unknown primary, which are mostly adenocarcinomas or squamous cell carcinomas, therefore require more sophisticated methodologies of classification. Here, we report a multiplex protein profiling-based approach for the classification of fresh frozen and formalin-fixed paraffin-embedded (FFPE) cancer tissue samples using the digital western blot technique DigiWest. A DigiWest-compatible FFPE extraction protocol was developed, and a total of 634 antibodies were tested in an initial set of 16 FFPE samples covering tumors from different origins. Of the 303 detected antibodies, 102 yielded significant correlation of signals in 25 pairs of fresh frozen and FFPE primary tumor samples, including head and neck squamous cell carcinomas (HNSC), lung squamous cell carcinomas (LUSC), lung adenocarcinomas (LUAD), colorectal adenocarcinomas (COAD), and pancreatic adenocarcinomas (PAAD). For this signature of 102 analytes (covering 88 total proteins and 14 phosphoproteins), a support vector machine (SVM) algorithm was developed. This allowed for the classification of the tissue of origin for all five tumor types studied here with high overall accuracies in both fresh frozen (90.4%) and FFPE (77.6%) samples. In addition, the SVM classifier reached an overall accuracy of 88% in an independent validation cohort of 25 FFPE tumor samples. Our results indicate that DigiWest-based protein profiling represents a valuable method for cancer classification, yielding conclusive and decisive data not only from fresh frozen specimens but also FFPE samples, thus making this approach attractive for routine clinical applications.

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Multiplex profiling identifies clinically relevant signalling proteins in an isogenic prostate cancer model of radioresistance

Cited by 8 publications

References 62 publications

Epigenetic regulation of TP53 is involved in prostate cancer radioresistance and DNA damage response signaling

Epigenetic regulation of TP53 is involved in prostate cancer radioresistance and DNA damage response signaling

Radioresistance Mechanisms in Prostate Cancer Cell Lines Surviving Ultra-Hypo-Fractionated EBRT: Implications and Possible Clinical Applications

Multiclass cancer classification in fresh frozen and formalin-fixed paraffin-embedded tissue by DigiWest multiplex protein analysis

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