Peptidomimetic targeting of critical androgen receptor–coregulator interactions in prostate cancer

Ravindranathan, Preethi; Lee, Tae Kyung; Yang, Lin; Centenera, Margaret M.; Butler, Lisa M.; Tilley, Wayne D.; Hsieh, Jer Tsong; Ahn, Jung Mo; Raj, Ganesh V.

doi:10.1038/ncomms2912

Cited by 128 publications

(126 citation statements)

References 41 publications

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“…Peptidomimetics combine the specificity of peptides with the desirable pharmacological attributes of small molecules, such as stability and bioavailability. The peptidomimetic D2 was designed to mimic the LXXLL motif, which is found in many nuclear receptor coregulators (Ravindranathan et al 2013). D2 effectively disrupted the interaction between AR and the coactivator PELP1, which contains 10 LXXLL motifs, thereby blocking AR nuclear localization and transactivation and prostate cancer growth (Ravindranathan et al 2013).…”

Section: Targeting Androgen Receptor Coregulatorsmentioning

confidence: 99%

“…The peptidomimetic D2 was designed to mimic the LXXLL motif, which is found in many nuclear receptor coregulators (Ravindranathan et al 2013). D2 effectively disrupted the interaction between AR and the coactivator PELP1, which contains 10 LXXLL motifs, thereby blocking AR nuclear localization and transactivation and prostate cancer growth (Ravindranathan et al 2013). Although numerous other LXXLL-derived peptidomimetic inhibitors of AR:coactivator interactions are in pre-clinical development (Biron & Bedard 2015), it must be noted that targeting this motif may be an ineffective strategy in the case of AR-V-driven disease (Ravindranathan et al 2013).…”

Section: Targeting Androgen Receptor Coregulatorsmentioning

confidence: 99%

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Androgen receptor signaling in castration-resistant prostate cancer: a lesson in persistence

Coutinho¹,

Day²,

Tilley³

et al. 2016

Endocrine-Related Cancer

151

122

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The androgen receptor (AR) signaling axis drives all stages of prostate cancer, including the lethal, drug-resistant form of the disease termed castration-resistant prostate cancer (CRPC), which arises after failure of androgen deprivation therapy (ADT). Persistent AR activity in spite of ADT and the second-generation AR-targeting agents enzalutamide and abiraterone is achieved in many cases by direct alterations to the AR signaling axis. Herein, we provide a detailed description of how such alterations contribute to the development and progression of CRPC. Aspects of this broad and ever-evolving field specifically addressed in this review include: the etiology and significance of increased AR expression; the frequency and role of gain-of-function mutations in the AR gene; the function of constitutively active, truncated forms of the AR termed AR variants and the clinical relevance of alterations to the activity and expression of AR coregulators. Additionally, we examine the novel therapeutic strategies to inhibit these classes of therapy resistance mechanisms, with an emphasis on emerging agents that act in a manner distinct from the current ligand-centric approaches. Throughout, we discuss how the central role of AR in prostate cancer and the constant evolution of the AR signaling axis during disease progression represent archetypes of two key concepts in oncology, oncogene addiction and therapy-mediated selection pressure.

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Section: Targeting Androgen Receptor Coregulatorsmentioning

confidence: 99%

Section: Targeting Androgen Receptor Coregulatorsmentioning

confidence: 99%

Androgen receptor signaling in castration-resistant prostate cancer: a lesson in persistence

Coutinho¹,

Day²,

Tilley³

et al. 2016

Endocrine-Related Cancer

151

122

View full text Add to dashboard Cite

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“…The LxxLL domains of PELP1 have distinct binding specificities: for example, estrogen receptor-alpha (ERa) preferentially interacts with the fourth and fifth LxxLL domains to mediate PELP1 signaling (Barletta et al 2004). Although the specific LxxLL domains of PELP1 that interact with androgen receptor (AR), progesterone receptor (PR), glucocorticoid receptor (GR), or other SRs have not been characterized, they are distinct from the fourth LxxLL domain of PELP1 (Barletta et al 2004, Yang et al 2012, Ravindranathan et al 2013.…”

Section: Lxxll Domainsmentioning

confidence: 99%

“…PELP1 is widely expressed in various tissues, with the highest levels being measured in the brains, testes, ovaries, and uteri of mice (Vadlamudi et al 2001). Dysregulation of PELP1 expression has been observed in breast, ovarian, endometrial, brain, and prostate cancers (Dimple et al 2008, Kefalopoulou et al 2012, Wan & Li 2012, Yang et al 2012, Ravindranathan et al 2013. PELP1 is involved in both genomic and extranuclear signaling pathways (Boonyaratanakornkit 2011, Girard et al 2013, Renoir et al 2013.…”

Section: Introductionmentioning

confidence: 99%

The social network of PELP1 and its implications in breast and prostate cancers

Gonugunta¹,

Lu²,

Sareddy³

et al. 2014

Endocrine-Related Cancer

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Proline, glutamic acid-and leucine-rich protein 1 (PELP1) is a multi-domain scaffold protein that serves as a platform for various protein-protein interactions between steroid receptors (SRs) and signaling factors and cell cycle, transcriptional, cytoskeletal, and epigenetic remodelers. PELP1 is known to be a coregulator of transcription and participates in the nuclear and extranuclear functions of SRs, ribosome biogenesis, and cell cycle progression. The expression and localization of PELP1 are dysregulated in hormonal cancers including breast and prostate cancers. This review focuses on the interactive functions and therapeutic and prognostic significance of PELP1 in breast and prostate cancers.

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“…15,16 PELP1 functions as a coregulator for several nuclear receptors such as estrogen receptor (ER), androgen receptor (AR) and progesterone receptor (PR), and transcription factors such as STAT3, AP1 and E2F. [17][18][19] PELP1 associates with the chromatin 20 and interacts with histone-modifying complexes 17 including acetylases (CBP/P300), 21 methylases (SETDB1 and MLL1), 22,23 demethylases (KDM1) 24 and deacetylases (HDAC2 and MTA1). 17 It promotes cell proliferation by enhancing G1 to S phase progression via its interactions with the pRb/E2F pathway.…”

mentioning

confidence: 99%

Proline, glutamic acid and leucine-rich protein-1 is essential for optimal p53-mediated DNA damage response

et al. 2014

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, glutamic acid-and leucine-rich protein-1 (PELP1) is a scaffolding oncogenic protein that functions as a coregulator for a number of nuclear receptors. p53 is an important transcription factor and tumor suppressor that has a critical role in DNA damage response (DDR) including cell cycle arrest, repair or apoptosis. In this study, we found an unexpected role for PELP1 in modulating p53-mediated DDR. PELP1 is phosphorylated at Serine1033 by various DDR kinases like ataxia-telangiectasia mutated, ataxia telangiectasia and Rad3-related or DNAPKc and this phosphorylation of PELP1 is important for p53 coactivation functions. PELP1-depleted p53 (wild-type) breast cancer cells were less sensitive to various genotoxic agents including etoposide, camptothecin or c-radiation. PELP1 interacts with p53, functions as p53-coactivator and is required for optimal activation of p53 target genes under genomic stress. Overall, these studies established a new role of PELP1 in DDRs and these findings will have future implications in our understanding of PELP1's role in cancer progression. Cell Death and Differentiation (2014) 21, 1409-1418; doi:10.1038/cdd.2014.55; published online 2 May 2014 p53 is considered as the guardian of genomic integrity and has an important role in initiating cellular response to various genomic stresses such as cell cycle arrest, senescence, DNA repair and apoptosis.1,2 Loss of p53 or mutations in p53 is observed in 450% of the cases of all cancers.3-5 Stabilization of p53 upon genomic stress and activation of its transcription functions are vital for its central role in the DNA damage/ genomic stress response and in its tumor-suppressive functions.6,7 Upon genomic stress, p53 is stabilized and activated because of a decreased interaction with its E3-ligase MDM2.8 Activated p53 then upregulates expression of target genes, such as p21/WAF1, GADD45, PUMA and NOXA, all of which are important in the cellular decisions for cell cycle arrest or apoptosis. Post-translational modifications of p53, including phosphorylation, acetylation, ubiquitinylation and methylation, 10-12 and interactions with several cofactors 13,14 have a critical role in the p53-mediated transcriptional response to the DNA damage response (DDR). Proline-, glutamic acid-and leucine-rich protein-1 (PELP1), a large multi-domain protein, modulates a number of biological processes and several pathways including estrogen signaling, and cancer progression. 17 It promotes cell proliferation by enhancing G1 to S phase progression via its interactions with the pRb/E2F pathway.25 PELP1 localizes to the nucleolus and has an important role in ribosomal biogenesis.26 PELP1 signaling is also implicated in apoptosis and differentiation, and PELP1 functions as a coactivator of RXR homodimers and RXR-PPAR heterodimers.27 Although PELP1's role in both cell proliferation and differentiation is evident, it is not known how PELP1 would affect p53-mediated DDR functions and whether PELP1 status would affect sensitivity to various genomic stresses.In this study,...

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Peptidomimetic targeting of critical androgen receptor–coregulator interactions in prostate cancer

Cited by 128 publications

References 41 publications

Androgen receptor signaling in castration-resistant prostate cancer: a lesson in persistence

Androgen receptor signaling in castration-resistant prostate cancer: a lesson in persistence

The social network of PELP1 and its implications in breast and prostate cancers

Proline, glutamic acid and leucine-rich protein-1 is essential for optimal p53-mediated DNA damage response

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