The natural compound atraric acid suppresses androgen-regulated neo-angiogenesis of castration-resistant prostate cancer through angiopoietin 2

Ehsani, Marzieh; Bartsch, Sophie; Rasa, Seyed Mohammad Mahdi; Dittmann, Jessica; Pungsrinont, Thanakorn; Huettner, Soeren S; Kotolloshi, Roland; Schindler, Katrin; Ahmad, Aya; Mosig, Alexander S.; Adam, Lisa; Ori, Alessandro; Neri, Francesco; Berndt, Alexander; Grimm, Marc-Oliver; Baniahmad, Aria

doi:10.1038/s41388-022-02333-7

Cited by 13 publications

(8 citation statements)

References 65 publications

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“…Since also AR-antagonists change the cargo of exosomes, it suggests that AR-antagonists do not solely neutralize the AR but rather activate a distinct AR signaling including the regulation of protein content of exosomes. All AR-antagonists and the use of androgens at supraphysiological level induce cellular senescence in PCa cell lines and in patient-derived prostatectomy samples shown for AA and SAL [ 7 , 14 , 20 , 38 ]. It is possible that the AR-ligand mediated induced level of senescent cells within the cell population is one underlying mechanism of changed cargos in exosomes.…”

Section: Discussionmentioning

confidence: 99%

“…Bicalutamide (Bic), as the first-generation of AR-antagonists, and the subsequent second-generation of AR-antagonists, Enzalutamide (Enz) and Darolutamide (Dar), are established clinical interventions employed to block AR activity in PCa [ 5 ]. Besides these AR-antagonists, Atraric acid (AA) is the first natural compound identified and characterized as an AR-antagonist, suppressing PCa cell growth in cell culture, 3D spheroids and in xenograft mice [ 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

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The protein composition of exosomes released by prostate cancer cells is distinctly regulated by androgen receptor-antagonists and -agonist to stimulate growth of target cells

Atri Roozbahani,

Kokal-Ribaudo,

Heidari Horestani

et al. 2024

Cell Commun Signal

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Background Prostate cancer (PCa) is a prevalent malignancy in men worldwide, ranking as the second leading cause of cancer-related death in Western countries. Various PCa hormone therapies, such as androgen receptor (AR)-antagonists or supraphysiological androgen level (SAL) reduce cancer cell proliferation. However, treated cells may influence the growth of neighboring cells through secreted exosomes in the tumor microenvironment (TME). Here, the change of protein content of exosomes secreted from PCa cells through treatment with different AR-antagonists or SAL has been analyzed. Methods Isolation of exosomes via ultracentrifugation of treated human PCa LNCaP cells with AR-agonist and various AR-antagonists; analysis of cellular senescence by detection of senescence associated beta galactosidase activity (SA β-Gal); Western blotting and immunofluorescence staining; Mass spectrometry (MS-spec) of exosomes and bioinformatic analyses to identify ligand-specific exosomal proteins. Growth assays to analyze influence of exosomes on non-treated cells. Results MS-spec analysis identified ligand-specific proteins in exosomes. One thousand seventy proteins were up- and 52 proteins downregulated by SAL whereas enzalutamide upregulated 151 proteins and downregulated 42 exosomal proteins. The bioinformatic prediction indicates an up-regulation of pro-proliferative pathways. AR ligands augment hub factors in exosomes that include AKT1, CALM1, PAK2 and CTNND1. Accordingly, functional assays confirmed that the isolated exosomes from AR-ligand treated cells promote growth of untreated PCa cells. Conclusion The data suggest that the cargo of exosomes is controlled by AR-agonist and -antagonists and distinct among the AR-antagonists. Further, exosomes promote growth that might influence the TME. This finding sheds light into the complex interplay between AR signaling and exosome-mediated communication between PCa cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The protein composition of exosomes released by prostate cancer cells is distinctly regulated by androgen receptor-antagonists and -agonist to stimulate growth of target cells

Atri Roozbahani,

Kokal-Ribaudo,

Heidari Horestani

et al. 2024

Cell Commun Signal

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“…Atraric acid, a natural AR antagonist, inhibits proliferation and induces cellular senescence in cell culture, in both androgen dependent (LNCaP) and castration resistant (C4-2) PCa cells, as well as ex vivo in human PCa tumoroids derived from prostatectomies [ 91 , 101 ]. Interestingly, atraric acid inhibits both wild-type and of those AR mutants that mediate resistance to AR antagonists such as bicalutamide and enzalutamide [ 101 ]. Atraric acid inhibits AR transactivation and increases cytosolic localized AR.…”

Section: Therapy-induced Cellular Senescence In Pcamentioning

confidence: 99%

Distinct mechanisms mediating therapy-induced cellular senescence in prostate cancer

et al. 2022

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Background Prostate cancer (PCa) is an age-related malignancy in men with a high incidence rate. PCa treatments face many obstacles due to cancer cell resistance and many bypassing mechanisms to escape therapy. According to the intricacy of PCa, many standard therapies are being used depending on PCa stages including radical prostatectomy, radiation therapy, androgen receptor (AR) targeted therapy (androgen deprivation therapy, supraphysiological androgen, and AR antagonists) and chemotherapy. Most of the aforementioned therapies have been implicated to induce cellular senescence. Cellular senescence is defined as a stable cell cycle arrest in the G1 phase and is one of the mechanisms that prevent cancer proliferation. Results In this review, we provide and analyze different mechanisms of therapy-induced senescence (TIS) in PCa and their effects on the tumor. Interestingly, it seems that different molecular pathways are used by cancer cells for TIS. Understanding the complexity and underlying mechanisms of cellular senescence is very critical due to its role in tumorigenesis. The most prevalent analyzed pathways in PCa as TIS are the p53/p21WAF1/CIP1, the p15INK4B/p16INK4A/pRb/E2F/Cyclin D, the ROS/ERK, p27Kip1/CDK/pRb, and the p27Kip1/Skp2/C/EBP β signaling. Despite growth inhibition, senescent cells are highly metabolically active. In addition, their secretome, which is termed senescence-associated secretory phenotype (SASP), affects within the tumor microenvironment neighboring non-tumor and tumor cells and thereby may regulate the growth of tumors. Induction of cancer cell senescence is therefore a double-edged sword that can lead to reduced or enhanced tumor growth. Conclusion Thus, dependent on the type of senescence inducer and the specific senescence-induced cellular pathway, it is useful to develop pathway-specific senolytic compounds to specifically targeting senescent cells in order to evict senescent cells and thereby to reduce SASP side effects.

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“…It appears that androgens can induce neo‐angiogenesis in prostate cancer. As a naturally occurring compound with anti‐cancer activity, atraric acid decreases expression level of angiopoietin 2 to inhibiting angiogenesis in prostate cancer suppression (Ehsani et al 2022). The current section focuses on the association between PI3K/Akt signaling and angiogenesis in prostate cancer progression.…”

Section: Pi3k/akt and Angiogenesismentioning

confidence: 99%

Targeting PI3K/Akt signaling in prostate cancer therapy

Hashemi

Taheriazam

Daneii

et al. 2022

J. Cell Commun. Signal.

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Urological cancers have obtained much attention in recent years due to their mortality and morbidity. The most common and malignant tumor of urological cancers is prostate cancer that imposes high socioeconomic costs on public life and androgen‐deprivation therapy, surgery, and combination of chemotherapy and radiotherapy are employed in its treatment. PI3K/Akt signaling is an oncogenic pathway responsible for migration, proliferation and drug resistance in various cancers. In the present review, the role of PI3K/Akt signaling in prostate cancer progression is highlighted. The activation of PI3K/Akt signaling occurs in prostate cancer, while PTEN as inhibitor of PI3K/Akt shows down‐regulation. Stimulation of PI3K/Akt signaling promotes survival of prostate tumor cells and prevents apoptosis. The cell cycle progression and proliferation rate of prostate tumor cells increase by PI3K/Akt signaling induction. PI3K/Akt signaling stimulates EMT and enhances metastasis of prostate tumor cells. Silencing PI3K/Akt signaling impairs growth and metastasis of prostate tumor cells. Activation of PI3K/Akt signaling mediates drug resistance and reduces radio‐sensitivity of prostate tumor cells. Anti‐tumor compounds suppress PI3K/Akt signaling in impairing prostate tumor progression. Furthermore, upstream regulators such as miRNAs, lncRNAs and circRNAs regulate PI3K/Akt signaling and it has clinical implications for prostate cancer patients.

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The natural compound atraric acid suppresses androgen-regulated neo-angiogenesis of castration-resistant prostate cancer through angiopoietin 2

Cited by 13 publications

References 65 publications

The protein composition of exosomes released by prostate cancer cells is distinctly regulated by androgen receptor-antagonists and -agonist to stimulate growth of target cells

The protein composition of exosomes released by prostate cancer cells is distinctly regulated by androgen receptor-antagonists and -agonist to stimulate growth of target cells

Distinct mechanisms mediating therapy-induced cellular senescence in prostate cancer

Targeting PI3K/Akt signaling in prostate cancer therapy

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