Role of Epigenetic Therapy in the Modulation of Tumor Growth and Migration in Human Castration-Resistant Prostate Cancer Cells with Neuroendocrine Differentiation

Dicitore, Alessandra; Bacalini, Maria Giulia; Saronni, Davide; Gaudenzi, Germano; Cantone, Maria Celeste; Gelmini, Giulia; Grassi, Elisa; Gentilini, Davide; Borghi, Maria Orietta; Blasio, Anna Maria Di; Persani, Luca; Garagnani, Paolo; Franceschi, Claudio; Vitale, Giovanni

doi:10.1159/000518801

Cited by 3 publications

(2 citation statements)

References 51 publications

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“…It has been previously reported that DU-145 and PC-3 cells are androgen-independent cell lines [ 34 ], and C4-2B cells are androgen receptor-positive but androgen-independent [ 35 ]. All three cell lines possess a tendency to develop NE characteristics [ 36 , 37 ]. Thus, we employed SOX4-high-expressing DU-145 and PC-3 cells to construct SOX4-knockdown subclone cell lines and selected SOX4-low-expressing C4-2B cells to construct SOX4-overexpressing subclone cell lines.…”

Section: Resultsmentioning

confidence: 99%

Targeting SOX4/PCK2 signaling suppresses neuroendocrine trans-differentiation of castration-resistant prostate cancer

Jing,

Tao,

et al. 2024

Biol Direct

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Background Neuroendocrine prostate cancer (NEPC), a lethal subset of prostate cancer (PCa), is characterized by loss of AR signaling and resistance to AR-targeted therapy. While it is well reported that second-generation AR blockers induce neuroendocrine (NE) trans-differentiation of castration-resistant prostate cancer (CRPC) to promote the occurrence of NEPC, and pluripotent transcription factors might be potential regulators, the underlying molecular mechanisms remain unclear. Methods We analyzed the data from public databsets to screen candidate genes and then focused on SOX4, a regulator of NE trans-differentiation. The expression changes of SOX4 and its relationship with tumor progression were validated in clinical tumor tissues. We evaluated malignant characteristics related to NEPC in prostate cancer cell lines with stable overexpression or knockdown of SOX4 in vitro. Tumor xenografts were analyzed after inoculating the relevant cell lines into nude mice. RNA-seq, ATAC-seq, non-targeted metabolomics analysis, as well as molecular and biochemical assays were carried out to determine the mechanism. Results We screened public datasets and identified that expression of SOX4 was significantly elevated in NEPC. Overexpressing SOX4 in C4-2B cells increased cell proliferation and migration, upregulated the expression of NE marker genes, and inhibited AR expression. Consistently, inhibition of SOX4 expression in DU-145 and PC-3 cells reduced the above malignant phenotypes and repressed the expression of NE marker genes. For the in vivo assay, we found that knockdown of SOX4 inhibited tumor growth of subcutaneous xenografts in castrated nude mice which were concomitantly treated with enzalutamide (ENZ). Mechanically, we identified that one of the key enzymes in gluconeogenesis, PCK2, was a novel target of SOX4. The activation of carbohydrate metabolism reprogramming by SOX4 could promote NE trans-differentiation via the SOX4/PCK2 pathway. Conclusions Our findings reveal that SOX4 promotes NE trans-differentiation both in vitro and in vivo via directly enhancing PCK2 activity to activate carbohydrate metabolism reprogramming. The SOX4/PCK2 pathway and its downstream changes might be novel targets for blocking NE trans-differentiation.

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Section: Resultsmentioning

confidence: 99%

Targeting SOX4/PCK2 signaling suppresses neuroendocrine trans-differentiation of castration-resistant prostate cancer

Jing,

Tao,

et al. 2024

Biol Direct

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“…After 3 days of incubation, cell culture medium was replaced with a fresh one containing vehicle or drug at different concentrations. After 6 days, cells were analyzed using MTT (for NCI-H727 and UMC-11) or MTS (for NCI-H835 and NCI-H720) assays, as previously described [27,28].…”

Section: Cell Viability Assaymentioning

confidence: 99%

Antitumor Activity of Axitinib in Lung Carcinoids: A Preclinical Study

Dicitore,

Gaudenzi,

Carra

et al. 2023

Cancers

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Lung carcinoids (LCs) comprise well-differentiated neuroendocrine tumors classified as typical (TCs) and atypical (ACs) carcinoids. Unfortunately, curative therapies remain elusive for metastatic LCs, which account for 25–30% of cases. This study evaluated the antitumor activity of axitinib (AXI), a second-generation tyrosine kinase inhibitor selectively targeting vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2, VEGFR-3) in human lung TC (NCI-H727, UMC-11, NCI-H835) and AC (NCI-H720) cell lines. In vitro and in vivo (zebrafish) assays were performed following AXI treatment to gather several read-outs about cell viability, cell cycle, the secretion of proangiogenic factors, apoptosis, tumor-induced angiogenesis and migration. AXI demonstrated relevant antitumor activity in human LC cells, with pronounced effects observed in UMC-11 and NCI-H720, characterized by cell cycle perturbation and apoptosis induction. AXI significantly hindered tumor induced-angiogenesis in Tg(fli1a:EGFP)y1 zebrafish embryos implanted with all LC cell lines and also reduced the invasiveness of NCI-H720 cells, as well as the secretion of several proangiogenic factors. In conclusion, our study provides initial evidence supporting the potential anti-tumor activity of AXI in LC, offering a promising basis for future investigations in mammalian animal models and, eventually, progressing to clinical trials.

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Up-Regulation of PSMA Expression In Vitro as Potential Application in Prostate Cancer Therapy

et al. 2023

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Possibilities to improve the therapeutic efficacy of Lu-177–PSMA-617 radionuclide therapy by modulation of target expression are being investigated. Knowledge on regulatory factors that promote prostate cancer (PCa) progression may contribute to targeting prostate cancer more effectively. We aimed at the stimulation of PCa cell lines using the substances 5-aza-2′-deoxycitidine (5-aza-dC) and valproic acid (VPA) to achieve increased prostate-specific membrane antigen (PSMA) expression. PC3, PC3-PSMA, and LNCaP cells were incubated with varying concentrations of 5-aza-dC and VPA to investigate the cell-bound activity of Lu-177–PSMA-617. Stimulation effects on both the genetically modified cell line PC3-PSMA and the endogenously PSMA-expressing LNCaP cells were demonstrated by increased cellular uptake of the radioligand. For PC3-PSMA cells, the fraction of cell-bound radioactivity was enhanced by about 20-fold compared to that of the unstimulated cells. Our study reveals an increased radioligand uptake mediated by stimulation for both PC3-PSMA and LNCaP cell lines. In perspective of an enhanced PSMA expression, the present study might contribute to advanced radionuclide therapy approaches that improve the therapeutic efficacy, as well as combined treatment options.

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Role of Epigenetic Therapy in the Modulation of Tumor Growth and Migration in Human Castration-Resistant Prostate Cancer Cells with Neuroendocrine Differentiation

Cited by 3 publications

References 51 publications

Targeting SOX4/PCK2 signaling suppresses neuroendocrine trans-differentiation of castration-resistant prostate cancer

Targeting SOX4/PCK2 signaling suppresses neuroendocrine trans-differentiation of castration-resistant prostate cancer

Antitumor Activity of Axitinib in Lung Carcinoids: A Preclinical Study

Up-Regulation of PSMA Expression In Vitro as Potential Application in Prostate Cancer Therapy

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