Preferential induction of G1 arrest in androgen-responsive human prostate cancer cells by androgen receptor signaling antagonists DL3 and antiandrogen bicalutamide

Lu, Shan; Tan, Zongqin; Wortman, Matthew D.; Dong, Zhongyun

doi:10.1016/j.canlet.2010.07.012

Cited by 5 publications

(4 citation statements)

References 33 publications

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“…Similar results were obtained with TRAMP-C2 cells [24], and more recently in a AR+/PDX adenocarcinoma model (NSG-TM00298 [25]). This is apparently a critical survival mechanism of AS-PCa cells that implement a DDR in order to arrest in G1 upon androgen deprivation-like treatment with bicalutamide (BIC) [36]. We have recently attributed the probable mechanisms causing this DDR activation to the role played by the AR as a replication licensing factor [37] in combination with the increased expression of TLK1B, and resulting activation of the NEK1>ATR>Chk1 axis [24], which is a key target of TLK1 [23].…”

Section: Nek1 Regulated the Stability Of Yapmentioning

confidence: 99%

NEK1 Phosphorylation of YAP Promotes Its Stabilization and Transcriptional Output

Khalil

Ghosh

Singh

et al. 2020

Cancers

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Most prostate cancer (PCa) deaths result from progressive failure in standard androgen deprivation therapy (ADT), leading to metastatic castration-resistant PCa (mCRPC); however, the mechanism and key players leading to this are not fully understood. While studying the role of tousled-like kinase 1 (TLK1) and never in mitosis gene A (NIMA)-related kinase 1 (NEK1) in a DNA damage response (DDR)-mediated cell cycle arrest in LNCaP cells treated with bicalutamide, we uncovered that overexpression of wt-NEK1 resulted in a rapid conversion to androgen-independent (AI) growth, analogous to what has been observed when YAP1 is overexpressed. We now report that overexpression of wt-NEK1 results in accumulation of YAP1, suggesting the existence of a TLK1>NEK1>YAP1 axis that leads to adaptation to AI growth. Further, YAP1 is co-immunoprecipitated with NEK1. Importantly, NEK1 was able to phosphorylate YAP1 on six residues in vitro, which we believe are important for stabilization of the protein, possibly by increasing its interaction with transcriptional partners. In fact, knockout (KO) of NEK1 in NT1 PCa cells resulted in a parallel decrease of YAP1 level and reduced expression of typical YAP-regulated target genes. In terms of cancer potential implications, the expression of NEK1 and YAP1 proteins was found to be increased and correlated in several cancers. These include PCa stages according to Gleason score, head and neck squamous cell carcinoma, and glioblastoma, suggesting that this co-regulation is imparted by increased YAP1 stability when NEK1 is overexpressed or activated by TLK1, and not through transcriptional co-expression. We propose that the TLK1>NEK1>YAP1 axis is a key determinant for cancer progression, particularly during the process of androgen-sensitive to -independent conversion during progression to mCRPC.

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Section: Nek1 Regulated the Stability Of Yapmentioning

confidence: 99%

NEK1 Phosphorylation of YAP Promotes Its Stabilization and Transcriptional Output

Khalil

Ghosh

Singh

et al. 2020

Cancers

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“…It can be speculated that the effect of the microtubule stabilizing drug docetaxel on the mitotic arrest and induction of apoptosis could be aided by the interference in the G2/M progression upon silencing of FGD4. The effect of Casodex, on the other hand, has been shown to be mediated by inhibition of G1 phase progression through inactivating AR transcriptional activation [52, 53] and induction of apoptosis through caspase dependent and independent pathways [54]. It is possible that silencing of FGD4 can also have a synergistic effect on the Casodex mediated reduction in cell viability through its effect on G2/M arrest.…”

Section: Discussionmentioning

confidence: 99%

Expression of FGD4 positively correlates with the aggressive phenotype of prostate cancer

et al. 2018

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BackgroundFGD4 (Frabin) is an F-actin binding protein with GTP/GDP exchange activity specific for CDC42. It is involved in reorganization of the actin cytoskeleton, which requires both actin binding and CDC42 activating function of FGD4. Expression of FGD4 is altered in patients with heterogeneous hereditary motor and sensory neuropathies as a result of demyelination of peripheral nerves.MethodsIn this study, we examined the expression of FGD4 in prostate cancer specimens using immunohistochemistry and studied the function of FGD4 in maintaining cell phenotype, behavior and drug sensitivity using overexpression and siRNA-based silencing approaches. We used Mann-Whitney test for comparative analysis of FGD4 expression.ResultsOur results show that the expression of FGD4 is upregulated in cancerous prostates compared to the luminal cells in benign prostatic hyperplasia, although the basal cells showed high staining intensities. We noted a gradual increase in the staining intensity of FGD4 with increasing aggressiveness of the disease. Inhibition of expression of FGD4 using siRNAs showed reduced proliferation and cell cycle arrest in G2/M phase of androgen dependent LNCaP-104S and androgen refractory PC-3 cells. Inhibition of FGD4 also resulted in reduced cell migration and CDC42 activities in PC-3 cells whereas, ectopic expression of FGD4 induced cell migration, altered expression of mesenchymal and epithelial markers and activation of CDC42/PAK signaling pathway. Reduced expression of FGD4 improved sensitivity of LNCaP-104S cells to the anti-androgen drug Casodex and PC-3 cells to the microtubule stabilizing drug docetaxel.ConclusionsOur data demonstrate a tumor promoting and a cell migratory function of FGD4 in prostate cancer cells and that inhibition of FGD4 expression enhances the response for both androgen-dependent and independent prostate cancer cells towards currently used prostate cancer drugs.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-5096-9) contains supplementary material, which is available to authorized users.

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“…The cells were trypsinized, fixated in 70% ethanol and stained with propidium iodide (Sigma) according to a protocol described before (33). Using a Beckman Instruments Coulter Epics XL flow cytometer (Analis), the fractions of cells in each phase of the cell cycle were quantified and analyzed with the System II software (Analis).…”

Section: Flow Cytometric Analysismentioning

confidence: 99%

Identification and Characterization of MEL-3, a Novel AR Antagonist That Suppresses Prostate Cancer Cell Growth

Helsen

Marchand

Chaltin

et al. 2012

Molecular Cancer Therapeutics

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Antiandrogens are an important component of prostate cancer therapy as the androgen receptor (AR) is the key regulator of prostate cancer growth and survival. Current AR antagonists, such as bicalutamide and hydroxyflutamide, have a low affinity for the AR and as a result block AR signaling insufficiently. Moreover, many patients develop a resistance for bicalutamide or hydroxyflutamide during therapy or show a clinical improvement after withdrawal of the antiandrogen. New and more effective AR antagonists are needed to ensure follow-up of these patients. We therefore developed a screening system to identify novel AR antagonists from a collection of compounds. MEL-3 [8-(propan-2-yl)-5,6-dihydro-4H-pyrazino[3,2,1-jk]carbazole] was selected as potent inhibitor of the AR and was further characterized in vitro. On different prostate cancer cell lines MEL-3 displayed an improved therapeutic profile compared with bicalutamide. Not only cell growth was inhibited but also the expression of androgen-regulated genes: PSA and FKBP5. Prostate cancer is often associated with mutated ARs that respond to a broadened spectrum of ligands including the current antiandrogens used in the clinic, hydroxyflutamide and bicalutamide. The activity of two mutant receptors (AR T877A and AR W741C) was shown to be reduced in presence of MEL-3, providing evidence that MEL-3 can potentially be a follow-up treatment for bicalutamide-and hydroxyflutamide-resistant patients. The mechanism of action of MEL-3 on the molecular level was further explored by comparing the structure-activity relationship of different chemical derivatives of MEL-3 with the in silico docking of MEL-3 derivatives in the binding pocket of the AR.

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Preferential induction of G1 arrest in androgen-responsive human prostate cancer cells by androgen receptor signaling antagonists DL3 and antiandrogen bicalutamide

Cited by 5 publications

References 33 publications

NEK1 Phosphorylation of YAP Promotes Its Stabilization and Transcriptional Output

NEK1 Phosphorylation of YAP Promotes Its Stabilization and Transcriptional Output

Expression of FGD4 positively correlates with the aggressive phenotype of prostate cancer

Identification and Characterization of MEL-3, a Novel AR Antagonist That Suppresses Prostate Cancer Cell Growth

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