The AR dependent cell cycle: Mechanisms and cancer relevance

Schiewer, Matthew J.; Augello, Michael A.; Knudsen, Karen E.

doi:10.1016/j.mce.2011.06.033

Cited by 49 publications

(41 citation statements)

References 167 publications

(216 reference statements)

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“…It is also unclear whether in LNCaP cells, a CaMKK2 driven cascade impinges upon cell cycle regulators in an AR-independent fashion (48 -50). Activity of the AR is critical for G 1 -S phase progression in PCa cells (45,46). Therefore our data that CaMKK2 knockdown reduces AR transactivation driven by two promoters (PSA and probasin) and phenotypically replicates the reductions in levels of phospho-RB and cyclin D1 protein but not cyclin D1 mRNA predicted from an action via the AR, strongly suggest that the CaMKK2-cell cycle regulation described here is AR-mediated to at least some degree.…”

Section: Discussionsupporting

confidence: 61%

“…The AR is a key regulator of PCa cellular proliferation and cell cycle transitions (45,46). We therefore investigated whether CaMKK2 could be a mediator of AR-dependent PCa cell cycle control.…”

Section: Resultsmentioning

confidence: 99%

“…Control of G 1 to S phase progression involves, among other mechanisms, up-regulation of cyclin D1 leading to increased formation of D1-cdk4/6 complexes, multisite ("hyper") phosphorylation and inactivation of the retinoblastoma (Rb) tumor suppressor, and consequent E2F-dependent expression of genes required for S phase entry. In PCa cells, androgen deprivation results in G 1 arrest, loss of cyclin D1 expression, and reduced Rb phosphorylation (45,46). Conversely, androgen stimulation of LNCaP cells up-regulates D-type cyclin expression and Rb phosphorylation.…”

Section: Resultsmentioning

confidence: 99%

“…Current conceptual models of signaling pathways active in PCa do not incorporate the CaMKK2 pathway (35,45,46,51). It will be of interest to explore this pathway both from the standpoint of delineating the downstream effectors responsible for transmitting enhanced CaMKK2 activity to the AR, the mechanism by which the activity of the AR is modulated, and how this is translated into altered cell cycle progression.…”

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

A Regulatory Feedback Loop Between Ca2+/Calmodulin-dependent Protein Kinase Kinase 2 (CaMKK2) and the Androgen Receptor in Prostate Cancer Progression

Karacosta

Foster

Azabdaftari

et al. 2012

Journal of Biological Chemistry

101

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Section: Discussionsupporting

confidence: 61%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

A Regulatory Feedback Loop Between Ca2+/Calmodulin-dependent Protein Kinase Kinase 2 (CaMKK2) and the Androgen Receptor in Prostate Cancer Progression

Karacosta

Foster

Azabdaftari

et al. 2012

Journal of Biological Chemistry

101

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“…Inhibition of androgen signaling as the primary mechanism of action of 17-AAG and bicalutamide is consistent with the associated molecular and cellular functions of cell cycle, cell death and lipid metabolism that were identified through genome-wide profiling. Cross-talk between AR and the cell cycle is well known to influence the mitogenic response to androgens (Schiewer et al 2012). Androgen-sensitive cells that are deprived of androgen exit the cell cycle and arrest in G0 (Knudsen et al 1998, Agus et al 1999, much like the cell cycle effects of combined 17-AAG and bicalutamide treatment observed here.…”

Section: Discussionsupporting

confidence: 53%

Co-targeting AR and HSP90 suppresses prostate cancer cell growth and prevents resistance mechanisms

Centenera¹,

Carter²,

Gillis³

et al. 2015

Endocrine-Related Cancer

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Persistent androgen receptor (AR) signaling in castration resistant prostate cancer (CRPC) underpins the urgent need for therapeutic strategies that better target this pathway. Combining classes of agents that target different components of AR signaling has the potential to delay resistance and improve patient outcomes. Many oncoproteins, including the AR, rely on the molecular chaperone heat shock protein 90 (Hsp90) for functional maturation and stability. In this study, enhanced anti-proliferative activity of the Hsp90 inhibitors 17-allylamino-demethoxygeldanamycin (17-AAG) and AUY922 in androgen-sensitive and CRPC cells was achieved when the agents were used in combination with AR antagonists bicalutamide or enzalutamide. Moreover, significant caspasedependent cell death was achieved using sub-optimal agent doses that individually have no effect. Expression profiling demonstrated regulation of a broadened set of AR target genes with combined 17-AAG and bicalutamide compared with the respective single agent treatments. This enhanced inhibition of AR signaling was accompanied by impaired chromatin binding and nuclear localization of the AR. Importantly, expression of the AR variant AR-V7 that is implicated in resistance to AR antagonists was not induced by combination treatment. Likewise, the heat shock response that is typically elicited with therapeutic doses of Hsp90 inhibitors, and is a potential mediator of resistance to these agents, was significantly reduced by combination treatment. In summary, the co-targeting strategy in this study more effectively inhibits AR signaling than targeting AR or HSP90 alone and prevents induction of key resistance mechanisms in prostate cancer cells. These findings merit further evaluation of this therapeutic strategy to prevent CRPC growth.

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Metastatic prostate cancer diagnosed by fine‐needle aspiration: Contemporary cytopathologic and biomarker assessment with clinical correlates

Cantley

Wang

Reichert

et al. 2022

Cancer Cytopathology

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Introduction The diagnosis of metastatic prostatic cancer (MPC) by fine needle aspiration (FNA) can usually be rendered by typical cytomorphologic and immunohistochemical (IHC) features. However, MPC diagnosis may be complicated by transformation to atypical phenotypes such as small cell carcinoma, typically under pressure from androgen deprivation therapy (ADT). Predictive and prognostic biomarkers can also be assessed by IHC. This study illustrates how careful assessment of cytologic and biomarker features may provide therapeutic and prognostic information in MPC. Design We reviewed our anatomic pathology archives for MPC diagnosed by FNA from January 2014 to June 2021. Clinical histories, cytology slides, and cell blocks were reviewed. Extensive IHC biomarker workup was performed, including markers of prostate lineage, cell‐cycle dysfunction, Ki‐67, neuroendocrine markers, PDL1, and androgen receptor splice variant 7. Cases were reclassified into three categories: conventional type, intermediary type, and high‐grade neuroendocrine carcinoma (HGNC). Results Eighteen patients were identified. Twelve had conventional MPC, including six of six ADT‐naive patients. Six of twelve (50%) with prior ADT were reclassified as intermediary or HGNC. Four intermediary cases included two with squamous differentiation and two with pro‐proliferative features. Two HGNC cases had typical small cell carcinoma cytomorphology. Expression of PDL1 was identified in two cases and ARv7 in three cases. Five of five intermediary and HGNC patients died of disease versus six of eleven with with conventional type. Conclusions Aggressive cytomorphologic variants were commonly identified in patients with prior ADT. Identification of nonconventional cytomorphology and increased proliferation can provide important prognostic information. Recognition of these changes is important for an accurate diagnosis, and the identification of high‐grade variants can affect therapeutic decision‐making. Clinically actionable biomarkers such as PDL1 and ARv7 can be assessed by IHC.

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The AR dependent cell cycle: Mechanisms and cancer relevance

Cited by 49 publications

References 167 publications

A Regulatory Feedback Loop Between Ca2+/Calmodulin-dependent Protein Kinase Kinase 2 (CaMKK2) and the Androgen Receptor in Prostate Cancer Progression

A Regulatory Feedback Loop Between Ca2+/Calmodulin-dependent Protein Kinase Kinase 2 (CaMKK2) and the Androgen Receptor in Prostate Cancer Progression

Co-targeting AR and HSP90 suppresses prostate cancer cell growth and prevents resistance mechanisms

Metastatic prostate cancer diagnosed by fine‐needle aspiration: Contemporary cytopathologic and biomarker assessment with clinical correlates

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