TGF‐β signaling and androgen receptor status determine apoptotic cross‐talk in human prostate cancer cells

Zhu, Meng-Lei; Partin, James; Bruckheimer, Elizabeth; Strup, Stephen E.; Kyprianou, Natasha

doi:10.1002/pros.20698

Cited by 46 publications

(39 citation statements)

References 32 publications

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“…7). Consistent with our current findings, it has previously been reported that TGF-b and AR signaling mutually promoted their respective signals in PC-3 and LNCaP cells in which AR and TGF-bR2 are overexpressed (Zhu et al 2008). However, in classical TGF-b-induced pathway activation, Smad3/4 functions as both an AR co-activator and co-repressor, suggesting a complex role for Smad3/4 pathway in regulating AR signaling (Kang et al 2002).…”

Section: Discussionsupporting

confidence: 91%

Crosstalk between epithelial-mesenchymal transition and castration resistance mediated by Twist1/AR signaling in prostate cancer

Shiota¹,

Itsumi²,

Takeuchi³

et al. 2015

Endocrine-Related Cancer

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Although invasive and metastatic progression via the epithelial-mesenchymal transition (EMT) and acquisition of resistance to castration are both critical steps in prostate cancer, the molecular mechanism of this interaction remains unclear. In this study, we aimed to elucidate the interaction of signaling between castration resistance and EMT, and to apply this information to the development of a novel therapeutic concept using transforming growth factor-b (TGF-b) inhibitor SB525334 combined with androgen-deprivation therapy against prostate cancer using an in vivo model. This study revealed that an EMT inducer (TGF-b) induced full-length androgen receptor (AR) and AR variant expression. In addition, a highly invasive clone showed augmented full-length AR and AR variant expression as well as acquisition of castration resistance. Conversely, full-length AR and AR as well as Twist1 and mesenchymal molecules variant expression were up-regulated in castration-resistant LNCaP xenograft. Finally, TGF-b inhibitor suppressed Twist1 and AR expression as well as prostate cancer growth combined with castration. Taken together, these results demonstrate that Twist1/AR signaling was augmented in castration resistant as well as mesenchymal-phenotype prostate cancer, indicating the molecular mechanism of mutual and functional crosstalk between EMT and castration resistance, which may play a crucial role in prostate carcinogenesis and progression.

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Section: Discussionsupporting

confidence: 91%

Crosstalk between epithelial-mesenchymal transition and castration resistance mediated by Twist1/AR signaling in prostate cancer

Shiota¹,

Itsumi²,

Takeuchi³

et al. 2015

Endocrine-Related Cancer

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“…Taken together, these results suggest a favorable outcome from taxane and androgen deprivation combination therapy, and pro-survival and anti-apoptotic roles of AR signaling in response to treatment with taxanes. In addition, androgen and AR expression rendered prostate cancer cells resistant to TGF-b-induced apoptosis (Zhu et al 2008). Similarly, administration of androgen inhibited apoptosis induced by the Akt inhibitor LY294002, while the antiandrogen drug flutamide abolished the anti-apoptotic effect of androgen (Kumar et al 2011).…”

Section: Pro-survival and Anti-apoptotic Roles Of Ar Signaling In Promentioning

confidence: 98%

Pro-survival and anti-apoptotic properties of androgen receptor signaling by oxidative stress promote treatment resistance in prostate cancer

Shiota

Yokomizo

Naito

2012

Endocrine-Related Cancer

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Oxidative stress caused by an increase in reactive oxygen species levels or a decrease in cellular antioxidant capacity can evoke the modulation of various cellular events including androgen receptor (AR) signaling via direct or indirect interactions. In this review, we summarize the mechanisms of AR activation by oxidative stress including: i) AR overexpression; ii) AR activation by AR co-regulators or intracellular signal transduction pathways; iii) generation of AR mutations or splice variants; and iv) de novo androgen synthesis. AR signaling augmented by oxidative stress appears to contribute to pro-survival and anti-apoptotic effects in prostate cancer cells in response to androgen deprivation therapy. In addition, AR signaling suppresses anti-survival and pro-apoptotic effects in prostate cancer cells in response to various cytotoxic and tumorsuppressive interventions including taxanes and radiation through the modulation of bIII-tubulin and ataxia telangiectasia-mutated kinase expression respectively. Taken together, AR signaling appears to render prostate cancer cells refractory to various therapeutic interventions including castration, taxanes, and radiation, indicating that AR signaling is a comprehensive resistant factor and crucial target for prostate cancer treatment.

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“…46 It was hypothesized that EGF/EGFR and TGF-b 1 /TGF-b 1 RII pathways are involved in the acquisition of AIPC phenotype, either through an independent alternative proliferative stimulus, or through the interference with androgen receptor (AR) axis. 46,47 The prostate is an androgen-dependent (AD) organ that undergoes involution after castration. Isaacs and Cooffey 48 suggested that the shift from AD-to-AIPC may be because of residual stem cells not responsive to androgens, which will emerge after ADT under the appropriate growth stimulus.…”

Section: Discussionmentioning

confidence: 99%

Combined analysis of EGF+61G>A and TGFB1+869T>C functional polymorphisms in the time to androgen independence and prostate cancer susceptibility

et al. 2009

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Proliferative mechanisms involving the epidermal growth factor (EGF) and transforming growth factor beta (TGF-b 1 ) ligands are potential alternative pathways for prostate cancer (PC) progression to androgen independence (AI). Thus, the combined effect of EGF and TGFB1 functional polymorphisms might modulate tumor microenvironment and consequently its development. We studied EGF þ 61G4A and TGFB1 þ 869T4C functional polymorphisms in 234 patients with PC and 243 healthy individuals. Intermediate-and highproliferation genetic profile carriers have increased risk for PC (odds ratio (OR) ¼ 3.76, P ¼ 0.007 and OR ¼ 3.98, P ¼ 0.004, respectively), when compared with low proliferation individuals. Multivariate analysis showed a significantly lower time to AI in the high proliferation group, compared with the low/intermediate proliferation genetic profile carriers (HR ¼ 2.67, P ¼ 0.039), after adjustment for age, metastasis and stage. Results suggest that combined analysis of target genetic polymorphisms may contribute to the definition of cancer susceptibility and pharmacogenomic profiles. Combined blockage of key molecules in proliferation signaling pathways could be one of the most promising strategies for androgen-independent prostate cancer.

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TGF‐β signaling and androgen receptor status determine apoptotic cross‐talk in human prostate cancer cells

Cited by 46 publications

References 32 publications

Crosstalk between epithelial-mesenchymal transition and castration resistance mediated by Twist1/AR signaling in prostate cancer

Crosstalk between epithelial-mesenchymal transition and castration resistance mediated by Twist1/AR signaling in prostate cancer

Pro-survival and anti-apoptotic properties of androgen receptor signaling by oxidative stress promote treatment resistance in prostate cancer

Combined analysis of EGF+61G>A and TGFB1+869T>C functional polymorphisms in the time to androgen independence and prostate cancer susceptibility

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