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Androgen receptor drives cellular senescence.

Mirochnik Y, Veliceasa D, Williams L, Maxwell K, Yemelyanov A, Budunova I, Volpert OV - PLoS ONE (2012)

Bottom Line: While growth-inhibitory, tumor-suppressive AR effects have also been documented, the underlying mechanisms are poorly understood.Instead, AR induced p21, which subsequently reduced ΔN isoform of p63.The two pathways engaged in a cross-talk, likely via PML tumor suppressor, whose localization to senescence-associated chromatin foci was increased by AR activation.

View Article: PubMed Central - PubMed

Affiliation: Urology Department, Northwestern University, Chicago, Illinois, United States of America.

ABSTRACT
The accepted androgen receptor (AR) role is to promote proliferation and survival of prostate epithelium and thus prostate cancer progression. While growth-inhibitory, tumor-suppressive AR effects have also been documented, the underlying mechanisms are poorly understood. Here, we for the first time link AR anti-cancer action with cell senescence in vitro and in vivo. First, AR-driven senescence was p53-independent. Instead, AR induced p21, which subsequently reduced ΔN isoform of p63. Second, AR activation increased reactive oxygen species (ROS) and thereby suppressed Rb phosphorylation. Both pathways were critical for senescence as was proven by p21 and Rb knock-down and by quenching ROS with N-Acetyl cysteine and p63 silencing also mimicked AR-induced senescence. The two pathways engaged in a cross-talk, likely via PML tumor suppressor, whose localization to senescence-associated chromatin foci was increased by AR activation. All these pathways contributed to growth arrest, which resolved in senescence due to concomitant lack of p53 and high mTOR activity. This is the first demonstration of senescence response caused by a nuclear hormone receptor.

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Molecular mechanism of the AR-induced senescence.This figure summarizes our findings. (A) mTOR activity in PC3-AR cells. Cells were treated with Dox alone (D) or in combination with DHT. Cell extracts were collected at days 3 and 5 of treatment and analyzed by Western blot for phosphorylated mTOR and p70S6K. Tubulin and total p70S6K served as loading controls. (B) Schematic representation of pathways leading to AR-indiced senescence: AR triggers two parallel pathways, necessary to ensure senescence and possibly engaged in a cross-talk: (1) Activated AR directly binds p21 promoter and thus causes protein expression and accumulation. P21 attenuates the levels of TAp63-α, increasing the number of PML nuclear bodies and causing senescence (2) AR enhances ROS production thus reducing phospho-Rb levels, while active Rb binds and sequesters E2F, causing senescence. Elevated p21 levels may additionally decrease phospho-Rb by blocking Cdks. Conversely, transcriptionally inactive Rb/E2F/HDAC complexes may be sequestered in PML bodies to maintain irreversible growth arrest/senescence. These pathways cumulatively contribute to quiescence, which progresses to senescence due to constitutive high mTOR activity.
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pone-0031052-g007: Molecular mechanism of the AR-induced senescence.This figure summarizes our findings. (A) mTOR activity in PC3-AR cells. Cells were treated with Dox alone (D) or in combination with DHT. Cell extracts were collected at days 3 and 5 of treatment and analyzed by Western blot for phosphorylated mTOR and p70S6K. Tubulin and total p70S6K served as loading controls. (B) Schematic representation of pathways leading to AR-indiced senescence: AR triggers two parallel pathways, necessary to ensure senescence and possibly engaged in a cross-talk: (1) Activated AR directly binds p21 promoter and thus causes protein expression and accumulation. P21 attenuates the levels of TAp63-α, increasing the number of PML nuclear bodies and causing senescence (2) AR enhances ROS production thus reducing phospho-Rb levels, while active Rb binds and sequesters E2F, causing senescence. Elevated p21 levels may additionally decrease phospho-Rb by blocking Cdks. Conversely, transcriptionally inactive Rb/E2F/HDAC complexes may be sequestered in PML bodies to maintain irreversible growth arrest/senescence. These pathways cumulatively contribute to quiescence, which progresses to senescence due to constitutive high mTOR activity.

Mentions: Growth arrest may be resolved via quiescence or senescence and the choice is dictated by mTOR activity. In the absence of p53, low mTOR activity allows cells to remain quiescent while high mTOR activity promotes senescence [41], [42], [43], [44]. In p53-negative PC3-AR cells AR activationdid not significantly alter mTOR activity remained high as was evidenced by phosphprylation levels (Fig. 7A). Phosphorylation of mTOR target, p70S6 kinase also remained high (not shown). We therefore conclude that Rb activation, increased p21, and decreased DNp63 together caused cell cycle arrest and senescence, with high mTOR activity, in the absence of p53 (Fig. 7B).


Androgen receptor drives cellular senescence.

Mirochnik Y, Veliceasa D, Williams L, Maxwell K, Yemelyanov A, Budunova I, Volpert OV - PLoS ONE (2012)

Molecular mechanism of the AR-induced senescence.This figure summarizes our findings. (A) mTOR activity in PC3-AR cells. Cells were treated with Dox alone (D) or in combination with DHT. Cell extracts were collected at days 3 and 5 of treatment and analyzed by Western blot for phosphorylated mTOR and p70S6K. Tubulin and total p70S6K served as loading controls. (B) Schematic representation of pathways leading to AR-indiced senescence: AR triggers two parallel pathways, necessary to ensure senescence and possibly engaged in a cross-talk: (1) Activated AR directly binds p21 promoter and thus causes protein expression and accumulation. P21 attenuates the levels of TAp63-α, increasing the number of PML nuclear bodies and causing senescence (2) AR enhances ROS production thus reducing phospho-Rb levels, while active Rb binds and sequesters E2F, causing senescence. Elevated p21 levels may additionally decrease phospho-Rb by blocking Cdks. Conversely, transcriptionally inactive Rb/E2F/HDAC complexes may be sequestered in PML bodies to maintain irreversible growth arrest/senescence. These pathways cumulatively contribute to quiescence, which progresses to senescence due to constitutive high mTOR activity.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3293868&req=5

pone-0031052-g007: Molecular mechanism of the AR-induced senescence.This figure summarizes our findings. (A) mTOR activity in PC3-AR cells. Cells were treated with Dox alone (D) or in combination with DHT. Cell extracts were collected at days 3 and 5 of treatment and analyzed by Western blot for phosphorylated mTOR and p70S6K. Tubulin and total p70S6K served as loading controls. (B) Schematic representation of pathways leading to AR-indiced senescence: AR triggers two parallel pathways, necessary to ensure senescence and possibly engaged in a cross-talk: (1) Activated AR directly binds p21 promoter and thus causes protein expression and accumulation. P21 attenuates the levels of TAp63-α, increasing the number of PML nuclear bodies and causing senescence (2) AR enhances ROS production thus reducing phospho-Rb levels, while active Rb binds and sequesters E2F, causing senescence. Elevated p21 levels may additionally decrease phospho-Rb by blocking Cdks. Conversely, transcriptionally inactive Rb/E2F/HDAC complexes may be sequestered in PML bodies to maintain irreversible growth arrest/senescence. These pathways cumulatively contribute to quiescence, which progresses to senescence due to constitutive high mTOR activity.
Mentions: Growth arrest may be resolved via quiescence or senescence and the choice is dictated by mTOR activity. In the absence of p53, low mTOR activity allows cells to remain quiescent while high mTOR activity promotes senescence [41], [42], [43], [44]. In p53-negative PC3-AR cells AR activationdid not significantly alter mTOR activity remained high as was evidenced by phosphprylation levels (Fig. 7A). Phosphorylation of mTOR target, p70S6 kinase also remained high (not shown). We therefore conclude that Rb activation, increased p21, and decreased DNp63 together caused cell cycle arrest and senescence, with high mTOR activity, in the absence of p53 (Fig. 7B).

Bottom Line: While growth-inhibitory, tumor-suppressive AR effects have also been documented, the underlying mechanisms are poorly understood.Instead, AR induced p21, which subsequently reduced ΔN isoform of p63.The two pathways engaged in a cross-talk, likely via PML tumor suppressor, whose localization to senescence-associated chromatin foci was increased by AR activation.

View Article: PubMed Central - PubMed

Affiliation: Urology Department, Northwestern University, Chicago, Illinois, United States of America.

ABSTRACT
The accepted androgen receptor (AR) role is to promote proliferation and survival of prostate epithelium and thus prostate cancer progression. While growth-inhibitory, tumor-suppressive AR effects have also been documented, the underlying mechanisms are poorly understood. Here, we for the first time link AR anti-cancer action with cell senescence in vitro and in vivo. First, AR-driven senescence was p53-independent. Instead, AR induced p21, which subsequently reduced ΔN isoform of p63. Second, AR activation increased reactive oxygen species (ROS) and thereby suppressed Rb phosphorylation. Both pathways were critical for senescence as was proven by p21 and Rb knock-down and by quenching ROS with N-Acetyl cysteine and p63 silencing also mimicked AR-induced senescence. The two pathways engaged in a cross-talk, likely via PML tumor suppressor, whose localization to senescence-associated chromatin foci was increased by AR activation. All these pathways contributed to growth arrest, which resolved in senescence due to concomitant lack of p53 and high mTOR activity. This is the first demonstration of senescence response caused by a nuclear hormone receptor.

Show MeSH
Related in: MedlinePlus