Proteomic analysis of extracellular vesicles identified PI3K pathway as a potential therapeutic target for cabazitaxel‐resistant prostate cancer

Hishida, Seiji; Kawakami, Kyojiro; Fujita, Yasunori; Kato, Taku; Takai, Manabu; Iinuma, Koji; Nakane, Keita; Tsuchiya, Tomohiro; Koie, Takuya; Miura, Yuri; Ito, Masafumi; Mizutani, Kosuke

doi:10.1002/pros.24138

Cited by 10 publications

(5 citation statements)

References 44 publications

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“…Although several studies have demonstrated the molecular profiling of taxane resistance [ 47 – 52 ], epigenetic modifiers have not been elucidated in taxane resistant CR-PCa. In an attempt to uncover the epigenetic modifiers (Fig.…”

Section: Discussionmentioning

confidence: 99%

Exploiting epigenetic targets to overcome taxane resistance in prostate cancer

Cevatemre,

Bulut,

Dedeoglu

et al. 2024

Cell Death Dis

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The development of taxane resistance remains a major challenge for castration resistant prostate cancer (CR-PCa), despite the effectiveness of taxanes in prolonging patient survival. To uncover novel targets, we performed an epigenetic drug screen on taxane (docetaxel and cabazitaxel) resistant CR-PCa cells. We identified BRPF reader proteins, along with several epigenetic groups (CBP/p300, Menin-MLL, PRMT5 and SIRT1) that act as targets effectively reversing the resistance mediated by ABCB1. Targeting BRPFs specifically resulted in the resensitization of resistant cells, while no such effect was observed on the sensitive compartment. These cells were successfully arrested at the G2/M phase of cell cycle and underwent apoptosis upon BRPF inhibition, confirming the restoration of taxane susceptibility. Pharmacological inhibition of BRPFs reduced ABCB1 activity, indicating that BRPFs may be involved in an efflux-related mechanism. Indeed, ChIP-qPCR analysis confirmed binding of BRPF1 to the ABCB1 promoter suggesting direct regulation of the ABCB1 gene at the transcriptional level. RNA-seq analysis revealed that BRPF1 knockdown affects the genes enriched in mTORC1 and UPR signaling pathways, revealing potential mechanisms underlying its functional impact, which is further supported by the enhancement of taxane response through the combined inhibition of ABCB1 and mTOR pathways, providing evidence for the involvement of multiple BRPF1-regulated pathways. Beyond clinical attributes (Gleason score, tumor stage, therapy outcome, recurrence), metastatic PCa databases further supported the significance of BRPF1 in taxane resistance, as evidenced by its upregulation in taxane-exposed PCa patients.

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Section: Discussionmentioning

confidence: 99%

Exploiting epigenetic targets to overcome taxane resistance in prostate cancer

Cevatemre,

Bulut,

Dedeoglu

et al. 2024

Cell Death Dis

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“…EV isolation. Highly-purified EVs were prepared by PS-affinity method as we described previously (16,17). In this study, we isolated EVs using MagCapture™ Exosome Isolation Kit PS Ver.…”

Section: Methodsmentioning

confidence: 99%

“…Desalting of peptides after trypsin digestion was conducted using styrene-divinylbenzene (SDB) stage-Tip. Proteomic analysis was performed as described previously (17). All data were analyzed for protein identification by Proteome Discoverer 2.4 software (Thermo Fisher Scientific).…”

Section: Nano Liquid Chromatography Tandem Mass Spectrometry (Nanolc-...mentioning

confidence: 99%

H19in Serum Extracellular Vesicles Reflects Resistance to AR Axis-targeted Therapy Among CRPC Patients

KATO,

KAWAKAMI,

MIZUTANI

et al. 2023

Cancer Genomics Proteomics

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Background/Aim: We aimed to evaluate the changes of androgen receptor (AR) signaling-related long non-coding RNAs (lncRNAs) in serum extracellular vesicles (EVs) from prostate cancer (PC) patients, in order to identify novel biomarkers for AR axis-targeted therapy (ARAT)resistance among castration-resistant PC (CRPC) patients. Patients and Methods: EVs were isolated from 2 patients before and after acquiring ARAT-resistance. RNA profiling of EVs was performed by RNA-sequencing. The expression levels of selected lncRNAs in EVs were analyzed by digital droplet PCR (ddPCR) in 58 localized and 14 metastatic PC patients at diagnosis, 7 ARAT-naïve and 6 ARAT-resistant CRPC patients. LncRNA H19 expression in PC tissue was examined using published data. In order to analyze the role of H19, the prognosis was analyzed in PC patients and proteomic analysis was performed in 22Rv1 PC cells. Results: RNA-sequencing revealed that AR-regulated RNAs were most enriched in EVs after acquiring ARAT-resistance. Among them, up-regulation of AR signaling-related lncRNAs (PCAT1, H19, HOXA-11AS, ZEB1-AS1, ARLNC1, PART1, CTBP1-AS and PCA3) was confirmed by ddPCR. H19 contained in EVs (EV-H19) was significantly increased among ARAT-resistant patients compared to ARAT-naïve CRPC or metastatic PC patients. In PC tissue, H19 was negatively correlated with AR protein and AR-activity score and up-regulated in neuroendocrine CRPC tissue with low AR expression. Furthermore, EV-H19 expression was significantly associated with worse outcome to androgendeprivation therapy. Proteomic analysis demonstrated that H19 knockdown enhanced PC-related protein expression. Conclusion: EV-H19 may negatively correlate with ARsignaling activity and could be a marker to diagnose ARATresistance among CRPC patients.Prostate cancer (PC) is the most commonly diagnosed male malignancy in the United States, with 268,490 new cases and the second leading cause of death with 34,500 deaths in 2022 (1). The five-year overall survival rate among localized and regional PC patients is over 99%, however, and it decreases to 31% among metastatic PC patients (1). Androgen receptor (AR)-signaling is a central axis in PC pathogenesis and androgen-deprivation therapy (ADT) is a common treatment for metastatic PC patients. ADT is temporarily effective; however, PC develops castration-resistant PC (CRPC) following ADT. It has been reported that AR-signaling is still activated in CRPC (2). For this reason, second generation androgen receptor axis-targeted therapy (ARAT; Abiraterone, Enzalutamide, Apalutamide and Darolutamide) is strongly recommended for CRPC patients by the National Comprehensive Cancer Network (NCCN) guidelines (3). Although ARAT improves the prognosis of CRPC, it has limited effect and CRPC patients develop ARAT-resistance (4). Prostate-specific antigen (PSA) is a reliable tumor monitoring marker for PC; however, it sometimes deviates from the disease state in CRPC patients who are receiving ARAT (5). Therefore, it is of great importance to identify novel biomarkers t...

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“…Human PC cell lines LNCaP and PC-3 obtained from JCRB Cell Bank (Osaka, Japan), and 22Rv1 purchased from The European Collection of Authenticated Cell Cultures were maintained in RPMI-1640 (FUJI-FILM Wako Pure Chemical, Osaka, Japan) containing penicillin, streptomycin and 10% fetal bovine serum (Equitech-Bio, Kerrville, TX). The docetaxel-resistant 22Rv1 cell line, 22Rv1DR, was previously described 18 . All cell culture experiments were performed using cells within less than 20 passages except for PC-3PRF cells stably transfected with Tet-on tetracycline-inducible perforin expression vector and docetaxel-resistant 22Rv1DR cells.…”

Section: Methodsmentioning

confidence: 99%

Gene therapy of prostate cancer using liposomes containing perforin expression vector driven by the promoter of prostate-specific antigen gene

Mizutani

Kawakami

Fujita

et al. 2022

Sci Rep

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Perforin secreted from cytotoxic lymphocytes plays a critical role in cancer immunosurveillance. The aim of this study was to investigate the therapeutic potential of liposomes containing perforin expression vector driven by the promotor of prostate-specific antigen (PSA). The anti-tumor effect of perforin was analyzed using prostate cancer (PC) PC-3 cells in which perforin expression was controlled by Tet-on system (PC-3PRF cells). Liposomes encapsulating PSA promoter-driven perforin expression vector (pLipo) were constructed for its specific expression in PC. The anti-tumor effect of pLipo was evaluated in vitro using docetaxel-resistant PC 22Rv1 PC cell line, 22Rv1DR, and PC-3 cells in the presence of human peripheral blood mono nuclear cells (PBMCs) and also in vivo using male nude mice bearing 22Rv1DR cell-derived tumor xenograft. Induction of perforin significantly inhibited growth of PC-3PRF cells. Treatment with pLipo induced perforin expression in 22Rv1DR cells expressing PSA but not in PC-3 cells lacking it. Treatment with pLipo at a low concentration was prone to inhibit growth of both cell lines and significantly inhibited growth of 22Rv1DR cells when co-incubated with PBMCs. The combined use of pLipo at a high concentration with PBMCs showed nearly complete inhibition of 22Rv1DR cell growth. Intravenous administration of pLipo via tail vein increased the level of perforin in tumor and serum and significantly decreased the tumor volume. Our results suggest that liposome-mediated PC-specific expression of perforin could be a novel therapy for advanced PC.

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Proteomic analysis of extracellular vesicles identified PI3K pathway as a potential therapeutic target for cabazitaxel‐resistant prostate cancer

Cited by 10 publications

References 44 publications

Exploiting epigenetic targets to overcome taxane resistance in prostate cancer

Exploiting epigenetic targets to overcome taxane resistance in prostate cancer

H19in Serum Extracellular Vesicles Reflects Resistance to AR Axis-targeted Therapy Among CRPC Patients

Gene therapy of prostate cancer using liposomes containing perforin expression vector driven by the promoter of prostate-specific antigen gene

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