ERK Regulates Calpain 2-induced Androgen Receptor Proteolysis in CWR22 Relapsed Prostate Tumor Cell Lines

Chen, Honglin; Libertini, Stephen J.; Wang, Yu; Kung, Hsing-Jien; Ghosh, Paramita M.; Mudryj, Maria

doi:10.1074/jbc.m109.049379

Cited by 32 publications

(27 citation statements)

References 38 publications

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“…The reemergence of filamin staining in CRPC cells (absent in localized cancer) is interesting given the prediction that cancer stem cells, which reinitiate CRPC tumor growth following androgendeprivation therapy, reside in the CK5þ8À basal cell compartment (28) and are shown here to coexpress FHL2 and filamin. Calpain expression and activity are higher under androgendepleted conditions (39), suggesting that androgen ablation therapy creates an environment that is not only highly selective for expression of ligand-independent variants including AR-V7 (40), but is also conducive for promoting nuclear FHL2. Therefore, of note are our data showing that FHL2 activates AR-V7 and both proteins colocalize in the nucleus of CRPC.…”

Section: Discussionmentioning

confidence: 99%

Regulation of the Transcriptional Coactivator FHL2 Licenses Activation of the Androgen Receptor in Castrate-Resistant Prostate Cancer

et al. 2013

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It is now clear that progression from localized prostate cancer to incurable castrate-resistant prostate cancer (CRPC) is driven by continued androgen receptor (AR), signaling independently of androgen. Thus, there remains a strong rationale to suppress AR activity as the single most important therapeutic goal in CRPC treatment. Although the expression of ligand-independent AR splice variants confers resistance to AR-targeted therapy and progression to lethal castrate-resistant cancer, the molecular regulators of AR activity in CRPC remain unclear, in particular those pathways that potentiate the function of mutant AR in CRPC. Here, we identify FHL2 as a novel coactivator of ligand-independent AR variants that are important in CRPC. We show that the nuclear localization of FHL2 and coactivation of the AR is driven by calpain cleavage of the cytoskeletal protein filamin, a pathway that shows differential activation in prostate epithelial versus prostate cancer cell lines. We further identify a novel FHL2-AR-filamin transcription complex, revealing how deregulation of this axis promotes the constitutive, ligand-independent activation of AR variants, which are present in CRPC. Critically, the calpain-cleaved filamin fragment and FHL2 are present in the nucleus only in CRPC and not benign prostate tissue or localized prostate cancer. Thus, our work provides mechanistic insight into the enhanced AR activation, most notably of the recently identified AR variants, including AR-V7 that drives CRPC progression. Furthermore, our results identify the first disease-specific mechanism for deregulation of FHL2 nuclear localization during cancer progression. These results offer general import beyond prostate cancer, given that nuclear FHL2 is characteristic of other human cancers where oncogenic transcription factors that drive disease are activated like the AR in prostate cancer. Cancer Res; 73(16); 5066-79. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 99%

Regulation of the Transcriptional Coactivator FHL2 Licenses Activation of the Androgen Receptor in Castrate-Resistant Prostate Cancer

et al. 2013

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“…This was based on the presence of a consensus calpain cleavage site in the AR hinge region and the observation that calpain-2 was able to cleave full-length AR protein in cell extracts derived from LNCaP and 22Rv1 cells, as well as the CRPCa CWR-R1 cell line which was also derived from the CWR22 xenograft model (Chen et al 2010; Libertini et al 2007). In addition, the full-length AR mRNA in 22Rv1 cells had been shown to be larger due to tandem duplication of AR exon 3, and this larger form of the AR appeared to have enhanced susceptibility to this mechanism of cleavage (Libertini et al 2007).…”

Section: Gain-of-function Ar Variants Discovered In the Cwr22 Pca Modelmentioning

confidence: 99%

Alternatively spliced androgen receptor variants

Dehm

Tindall

2011

Endocrine-Related Cancer

345

314

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Alternative splicing is an important mechanism for increasing functional diversity from a limited set of genes. De-regulation of this process is common in diverse pathologic conditions. The androgen receptor (AR) is a steroid receptor transcription factor with functions critical for normal male development as well as the growth and survival of normal and cancerous prostate tissue. Studies of AR function in androgen insensitivity syndrome (AIS) and prostate cancer (PCa) have demonstrated loss-of-function AR alterations in AIS, and gain-of-function AR alterations in PCa. Over the past two decades, AR gene alterations have been identified in various individuals with AIS, which disrupt normal AR splicing patterns and yield dysfunctional AR protein variants. More recently, altered AR splicing patterns have been identified as a mechanism of PCa progression and resistance to androgen-depletion therapy. Several studies have described the synthesis of alternatively spliced transcripts encoding truncated AR isoforms that lack the ligand-binding domain, which is the ultimate target of androgen depletion. Many of these truncated AR isoforms function as constitutively active, ligand-independent transcription factors that can support androgen-independent expression of AR target genes, as well as the androgen-independent growth of PCa cells. In this review, we will summarize the various alternatively spliced AR variants that have been discovered, with a focus on their role and origin in the pathologic conditions of AIS and PCa.

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“…The first mechanism forwarded for the production of the naturally occurring AR isoforms lacking LBD in CWR22 cell lines was calpain-mediated proteolysis [30, 31] although not without contradictory data [32]. However, it is now evident that splicing events generates some variants.…”

Section: Regulation Of Variant Isoform Productionmentioning

confidence: 99%

Androgen receptor and its splice variants in prostate cancer

Haile

Sadar

2011

Cell. Mol. Life Sci.

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Androgen receptor (AR) is a transcription factor that becomes active upon binding to androgens via its ligand-binding domain (LBD) or in response to signaling cascades initiated by growth factors and cytokines. The activity of AR requires regions within the N-terminal domain (NTD) in a manner that is distinct from the activation of related steroid hormone receptors. Unequivocal evidence has been amassed to consider that the AR axis is the most critical pathway for the progression of prostate cancer. Qualitatively distinct insight into AR pathobiology has been garnered that include AR-regulated gene expression is stage-specifically modulated during disease progression and that ligand requirement for AR activity could be rendered dispensable due to expression of constitutively active AR splice variants that are devoid of LBD. The recent appreciation of the clinical challenge that stems from non-gonadal androgens that are not inhibited by traditional hormonal therapies has been tangibly translated into the development of more potent drugs that can potentially lead towards achieving an androgen-free environment. The pre-clinical evidence that proves the AR NTD is a druggable target also forecasts further paradigm shift in the management of advanced prostate cancer. These advancements together with the identification of more robust AR antagonists and their promising clinical outcome has renewed the hope that targeting the AR pathway remains a sound strategy in the clinical management of prostate cancer. Here, we address these developments with a greater emphasis to the rapidly growing literature on AR splice variants.

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ERK Regulates Calpain 2-induced Androgen Receptor Proteolysis in CWR22 Relapsed Prostate Tumor Cell Lines

Cited by 32 publications

References 38 publications

Regulation of the Transcriptional Coactivator FHL2 Licenses Activation of the Androgen Receptor in Castrate-Resistant Prostate Cancer

Regulation of the Transcriptional Coactivator FHL2 Licenses Activation of the Androgen Receptor in Castrate-Resistant Prostate Cancer

Alternatively spliced androgen receptor variants

Androgen receptor and its splice variants in prostate cancer

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