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Article ; Online: PELP1: Structure, biological function and clinical significance.

Sareddy, Gangadhara Reddy / Vadlamudi, Ratna K

2016 Volume 585, Issue 1, Page(s) 128–134

Abstract: Proline-, glutamic acid-, and leucine-rich protein 1 (PELP1) is a scaffolding protein that functions as a coregulator of several transcription factors and nuclear receptors. Notably, the PELP1 protein has a histone-binding domain, recognizes histone ... ...

Abstract	Proline-, glutamic acid-, and leucine-rich protein 1 (PELP1) is a scaffolding protein that functions as a coregulator of several transcription factors and nuclear receptors. Notably, the PELP1 protein has a histone-binding domain, recognizes histone modifications and interacts with several chromatin-modifying complexes. PELP1 serves as a substrate of multitude of kinases, and phosphorylation regulates its functions in various complexes. Further, PELP1 plays essential roles in several pathways including hormonal signaling, cell cycle progression, ribosomal biogenesis, and the DNA damage response. PELP1 expression is upregulated in several cancers, its deregulation contributes to therapy resistance, and it is a prognostic biomarker for breast cancer survival. Recent evidence suggests that PELP1 represents a novel therapeutic target for many hormonal cancers. In this review, we summarized the emerging biological properties and functions of PELP1.
MeSH term(s)	Breast Neoplasms/genetics ; Breast Neoplasms/pathology ; Cell Cycle Checkpoints/genetics ; Co-Repressor Proteins/genetics ; Co-Repressor Proteins/metabolism ; DNA Repair/genetics ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Phosphorylation ; Protein Processing, Post-Translational/physiology ; Protein Structure, Tertiary ; Receptors, Cytoplasmic and Nuclear/genetics ; Signal Transduction/genetics ; Trans-Activators/genetics ; Transcription Factors/genetics ; Transcription Factors/metabolism
Chemical Substances	Co-Repressor Proteins ; PELP1 protein, human ; Receptors, Cytoplasmic and Nuclear ; Trans-Activators ; Transcription Factors
Language	English
Publishing date	2016-07-01
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	391792-7
ISSN	1879-0038 ; 0378-1119
ISSN (online)	1879-0038
ISSN	0378-1119
DOI	10.1016/j.gene.2016.03.017
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Article: PELP1: Structure, biological function and clinical significance

Sareddy, Gangadhara Reddy / Ratna K. Vadlamudi

Gene. 2016 July 01, v. 585, no. 1

2016

Abstract	Proline-, glutamic acid-, and leucine-rich protein 1 (PELP1) is a scaffolding protein that functions as a coregulator of several transcription factors and nuclear receptors. Notably, the PELP1 protein has a histone-binding domain, recognizes histone modifications and interacts with several chromatin-modifying complexes. PELP1 serves as a substrate of multitude of kinases, and phosphorylation regulates its functions in various complexes. Further, PELP1 plays essential roles in several pathways including hormonal signaling, cell cycle progression, ribosomal biogenesis, and the DNA damage response. PELP1 expression is upregulated in several cancers, its deregulation contributes to therapy resistance, and it is a prognostic biomarker for breast cancer survival. Recent evidence suggests that PELP1 represents a novel therapeutic target for many hormonal cancers. In this review, we summarized the emerging biological properties and functions of PELP1.
Keywords	biogenesis ; biomarkers ; breast neoplasms ; cell cycle ; DNA damage ; histones ; phosphorylation ; phosphotransferases (kinases) ; receptors ; scaffolding proteins ; therapeutics ; transcription factors
Language	English
Dates of publication	2016-0701
Size	p. 128-134.
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	391792-7
ISSN	1879-0038 ; 0378-1119
ISSN (online)	1879-0038
ISSN	0378-1119
DOI	10.1016/j.gene.2016.03.017
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Nonsteroidal anti-inflammatory drugs diclofenac and celecoxib attenuates Wnt/β-catenin/Tcf signaling pathway in human glioblastoma cells.

Sareddy, Gangadhara Reddy / Kesanakurti, Divya / Kirti, Puligurtha Bharadhwaja / Babu, Phanithi Prakash

Neurochemical research

2013 Volume 38, Issue 11, Page(s) 2313–2322

Abstract: Glioblastoma, the most common and aggressive primary brain tumors, carry a bleak prognosis and often recur even after standard treatment modalities. Emerging evidence suggests that deregulation of the Wnt/β-catenin/Tcf signaling pathway contributes to ... ...

Abstract	Glioblastoma, the most common and aggressive primary brain tumors, carry a bleak prognosis and often recur even after standard treatment modalities. Emerging evidence suggests that deregulation of the Wnt/β-catenin/Tcf signaling pathway contributes to glioblastoma progression. Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit tumor cell proliferation by suppressing Wnt/β-catenin/Tcf signaling in various human malignancies. In this study, we sought to inhibit Wnt/β-catenin/Tcf signaling in glioblastoma cells by the NSAIDs diclofenac and celecoxib. Both diclofenac and celecoxib significantly reduced the proliferation, colony formation and migration of human glioblastoma cells. Diclofenac and celecoxib downregulated β-catenin/Tcf reporter activity. Western and qRT-PCR analysis showed that diclofenac and celecoxib reduced the expression of β-catenin target genes Axin2, cyclin D1 and c-Myc. In addition, the cytoplasmic accumulation and nuclear translocation of β-catenin was significantly reduced following diclofenac and celecoxib treatment. Furthermore, diclofenac and celecoxib significantly increased phosphorylation of β-catenin and reduced the phosphorylation of GSK3β. These results clearly indicated that diclofenac and celecoxib are potential therapeutic agents against glioblastoma cells that act by suppressing the activation of Wnt/β-catenin/Tcf signaling.
MeSH term(s)	Anti-Inflammatory Agents, Non-Steroidal/pharmacology ; Celecoxib ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Diclofenac/pharmacology ; Glioblastoma/metabolism ; Humans ; Pyrazoles/pharmacology ; Sulfonamides/pharmacology ; TCF Transcription Factors/metabolism ; Wnt Proteins/metabolism ; Wnt Signaling Pathway/drug effects ; beta Catenin/metabolism
Chemical Substances	Anti-Inflammatory Agents, Non-Steroidal ; Pyrazoles ; Sulfonamides ; TCF Transcription Factors ; Wnt Proteins ; beta Catenin ; Diclofenac (144O8QL0L1) ; Celecoxib (JCX84Q7J1L)
Language	English
Publishing date	2013-09-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	199335-5
ISSN	1573-6903 ; 0364-3190
ISSN (online)	1573-6903
ISSN	0364-3190
DOI	10.1007/s11064-013-1142-9
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Article ; Online: The nonsteroidal anti-inflammatory drug celecoxib suppresses the growth and induces apoptosis of human glioblastoma cells via the NF-κB pathway.

Sareddy, Gangadhara Reddy / Geeviman, Khamushavalli / Ramulu, Chinta / Babu, Phanithi Prakash

Journal of neuro-oncology

2011 Volume 106, Issue 1, Page(s) 99–109

Abstract: Gliomas are devastating primary tumors of the central nervous system and tend to recur even after standard therapy. Celecoxib, the selective COX-2 nonsteroidal anti-inflammatory drug, has anti-neoplastic activity against several malignancies. ... ...

Abstract	Gliomas are devastating primary tumors of the central nervous system and tend to recur even after standard therapy. Celecoxib, the selective COX-2 nonsteroidal anti-inflammatory drug, has anti-neoplastic activity against several malignancies. Accumulating evidence suggests that several COX-2-independent mechanisms may also be involved in the anti-tumor effects of celecoxib. Deregulation of the NF-κB signaling pathway contributes to enhanced glioma cell survival, proliferation, and chemoresistance. In this study, we examined the efficacy of celecoxib in suppressing the growth of glioblastoma cell lines. We observed that treatment with celecoxib significantly reduced the proliferation of a variety of GBM cell lines in a dose-dependent manner and also induced apoptosis, which was evident from enhanced caspase-3 and 8 activity, PARP cleavage, and TUNEL positive cells. Celecoxib treatment significantly down-regulated TNF-α induced NF-κB nuclear translocation, NF-κB DNA binding activity, and NF-κB-dependent reporter gene expression in U373 and T98G cells in a dose-dependent manner. Furthermore, celecoxib suppressed IκBα degradation and phosphorylation and reduced IKK activity in a dose-dependent manner. This study provides evidence that celecoxib suppresses the growth of GBM cell lines partly by inhibiting the NF-κB signaling pathway.
MeSH term(s)	Anti-Inflammatory Agents, Non-Steroidal/pharmacology ; Apoptosis/drug effects ; Blotting, Western ; Brain Neoplasms/drug therapy ; Brain Neoplasms/pathology ; Celecoxib ; Cell Line, Tumor ; Cell Nucleus/metabolism ; Cell Survival/drug effects ; Colony-Forming Units Assay ; Coloring Agents ; Cyclooxygenase 2 Inhibitors/pharmacology ; Cytosol/metabolism ; Dose-Response Relationship, Drug ; Electrophoretic Mobility Shift Assay ; Fluorescent Antibody Technique ; Glioblastoma/drug therapy ; Glioblastoma/pathology ; Humans ; I-kappa B Proteins/metabolism ; In Situ Nick-End Labeling ; NF-kappa B/physiology ; Protein Transport ; Pyrazoles/pharmacology ; Signal Transduction/drug effects ; Sulfonamides/pharmacology ; Tetrazolium Salts ; Thiazoles ; Tumor Necrosis Factor-alpha/antagonists & inhibitors
Chemical Substances	Anti-Inflammatory Agents, Non-Steroidal ; Coloring Agents ; Cyclooxygenase 2 Inhibitors ; I-kappa B Proteins ; NF-kappa B ; Pyrazoles ; Sulfonamides ; Tetrazolium Salts ; Thiazoles ; Tumor Necrosis Factor-alpha ; thiazolyl blue (EUY85H477I) ; Celecoxib (JCX84Q7J1L)
Language	English
Publishing date	2011-08-17
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	604875-4
ISSN	1573-7373 ; 0167-594X
ISSN (online)	1573-7373
ISSN	0167-594X
DOI	10.1007/s11060-011-0662-x
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Zs.A 1825: Show issues

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Article ; Online: Wnt/beta-catenin/Tcf signaling pathway activation in malignant progression of rat gliomas induced by transplacental N-ethyl-N-nitrosourea exposure.

Sareddy, Gangadhara Reddy / Challa, Sundaram / Panigrahi, Manas / Babu, Phanithi Prakash

Neurochemical research

2009 Volume 34, Issue 7, Page(s) 1278–1288

Abstract: Although Wnt/beta-catenin/Tcf signaling pathway has been shown to be a crucial factor in the development of many cancers, little is known about its role in glioma malignancy. In the present study, we report the first evidence that Wnt/beta-catenin/Tcf ... ...

Abstract	Although Wnt/beta-catenin/Tcf signaling pathway has been shown to be a crucial factor in the development of many cancers, little is known about its role in glioma malignancy. In the present study, we report the first evidence that Wnt/beta-catenin/Tcf signaling pathway is constitutively activated in experimental gliomas induced by single transplacental dose of N-ethyl-N-nitrosourea (ENU). In the present study we analyzed ENU induced rat gliomas of different stages (P90, P135 and P180) for the expression of beta-catenin, Lef1, Tcf4 and their targets c-Myc, N-Myc and cyclin D1. Western blot analysis revealed upregulation of beta-catenin, Lef1, Tcf4, c-Myc, N-Myc and cyclin D1 in gliomas compared to controls and their levels were progressively increased from initial stage (P90) to progression stage (P180). In consistent with this, immunohistochemistry revealed the cytoplasmic and nuclear accumulation of beta-catenin, and nuclear positivity was evident for Lef1, Tcf4, c-Myc, N-Myc and cyclin D1. Based on these results, we conclude that Wnt/beta-catenin pathway may play a major role in the tumorigenesis and tumor progression in ENU induced rat gliomas.
MeSH term(s)	Animals ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/physiology ; Ethylnitrosourea ; Female ; Glioma/chemically induced ; Glioma/genetics ; Glioma/pathology ; Glioma/physiopathology ; Pregnancy ; Prenatal Exposure Delayed Effects ; Proto-Oncogene Proteins c-myc/metabolism ; Rats ; Signal Transduction/genetics ; Signal Transduction/physiology ; Transcription Factor 4 ; Transcription Factors/genetics ; Transcription Factors/physiology ; Wnt Proteins/genetics ; Wnt Proteins/physiology ; beta Catenin/genetics ; beta Catenin/physiology
Chemical Substances	DNA-Binding Proteins ; Proto-Oncogene Proteins c-myc ; Tcf4 protein, rat ; Transcription Factor 4 ; Transcription Factors ; Wnt Proteins ; beta Catenin ; Ethylnitrosourea (P8M1T4190R)
Language	English
Publishing date	2009-01-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	199335-5
ISSN	1573-6903 ; 0364-3190
ISSN (online)	1573-6903
ISSN	0364-3190
DOI	10.1007/s11064-008-9906-3
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Article ; Online: Brain-derived estrogen exerts anti-inflammatory and neuroprotective actions in the rat hippocampus.

Zhang, Quan-Guang / Wang, Ruimin / Tang, Hui / Dong, Yan / Chan, Alice / Sareddy, Gangadhara Reddy / Vadlamudi, Ratna K / Brann, Darrell W

Molecular and cellular endocrinology

2014 Volume 389, Issue 1-2, Page(s) 84–91

Abstract: 17β-estradiol (E2) has been implicated to play a critical role in neuroprotection, synaptic plasticity, and cognitive function. Classically, the role of gonadal-derived E2 in these events is well established, but the role of brain-derived E2 is less ... ...

Abstract	17β-estradiol (E2) has been implicated to play a critical role in neuroprotection, synaptic plasticity, and cognitive function. Classically, the role of gonadal-derived E2 in these events is well established, but the role of brain-derived E2 is less clear. To address this issue, we investigated the expression, localization, and modulation of aromatase and local E2 levels in the hippocampus following global cerebral ischemia (GCI) in adult ovariectomized rats. Immunohistochemistry (IHC) revealed that the hippocampal regions CA1, CA3 and dentate gyrus (DG) exhibited high levels of immunoreactive aromatase staining, with aromatase being co-localized primarily in neurons in non-ischemic animals. Following GCI, aromatase became highly expressed in GFAP-positive astrocytes in the hippocampal CA1 region at 2-3 days post GCI reperfusion. An ELISA for E2 and IHC for E2 confirmed the GCI-induced elevation of local E2 in the CA1 region and that the increase in local E2 occurred in astrocytes. Furthermore, central administration of aromatase antisense (AS) oligonucleotides, but not missense (MS) oligonucleotides, blocked the increase in aromatase and local E2 in astrocytes after GCI, and resulted in a significant increase in GCI-induced hippocampal CA1 region neuronal cell death and neuroinflammation. As a whole, these results suggest that brain-derived E2 exerts important neuroprotective and anti-inflammatory actions in the hippocampal CA1 region following GCI.
MeSH term(s)	Animals ; Anti-Inflammatory Agents/metabolism ; Aromatase/metabolism ; Astrocytes/metabolism ; Brain Ischemia/metabolism ; CA1 Region, Hippocampal/metabolism ; Cell Death/physiology ; Dentate Gyrus/metabolism ; Estradiol/metabolism ; Estrogens/metabolism ; Female ; Inflammation/metabolism ; Neurons/metabolism ; Neuroprotective Agents/metabolism ; Rats ; Rats, Sprague-Dawley
Chemical Substances	Anti-Inflammatory Agents ; Estrogens ; Neuroprotective Agents ; Estradiol (4TI98Z838E) ; Aromatase (EC 1.14.14.1)
Language	English
Publishing date	2014-02-06
Publishing country	Ireland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	187438-x
ISSN	1872-8057 ; 0303-7207
ISSN (online)	1872-8057
ISSN	0303-7207
DOI	10.1016/j.mce.2013.12.019
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Zs.A 1127: Show issues

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Article ; Online: Mustard NPR1, a mammalian IkappaB homologue inhibits NF-kappaB activation in human GBM cell lines.

Kesanakurti, Divya / Sareddy, Gangadhara Reddy / Babu, Phanithi Prakash / Kirti, Pulugurtha Bharadwaja

Biochemical and biophysical research communications

2009 Volume 390, Issue 3, Page(s) 427–433

Abstract: NF-kappaB activity is tightly regulated by IkappaB class of proteins. IkappaB proteins possess ankyrin repeats for binding to and inhibiting NF-kappaB. The regulatory protein, NPR1 from Brassica juncea possesses ankyrin repeats with sequence similarity ... ...

Abstract	NF-kappaB activity is tightly regulated by IkappaB class of proteins. IkappaB proteins possess ankyrin repeats for binding to and inhibiting NF-kappaB. The regulatory protein, NPR1 from Brassica juncea possesses ankyrin repeats with sequence similarity to IkappaBalpha subgroup. Therefore, we examined whether stably expressed BjNPR1 could function as IkappaB in inhibiting NF-kappaB in human glioblastoma cell lines. We observed that BjNPR1 bound to NF-kappaB and inhibited its nuclear translocation. Further, BjNPR1 expression down-regulated the NF-kappaB target genes iNOS, Cox-2, c-Myc and cyclin D1 and reduced the proliferation rate of U373 cells. Finally, BjNPR1 decreased the levels of pERK, pJNK and PKCalpha and increased the Caspase-3 and Caspase-8 activities. These results suggested that inhibition of NF-kappaB activation by BjNPR1 can be a promising therapy in NF-kappaB dependent pathologies.
MeSH term(s)	Active Transport, Cell Nucleus ; Amino Acid Sequence ; Ankyrin Repeat ; Cell Line, Tumor ; Cell Proliferation ; Cyclin D1/genetics ; Cyclooxygenase 2/genetics ; Down-Regulation ; Gene Expression ; Gene Expression Regulation ; Genes, Reporter ; Humans ; I-kappa B Proteins/genetics ; I-kappa B Proteins/metabolism ; Inflammation/therapy ; Molecular Sequence Data ; Mustard Plant/genetics ; Mustard Plant/metabolism ; NF-kappa B/antagonists & inhibitors ; NF-kappa B/metabolism ; Neoplasms/therapy ; Nitric Oxide Synthase Type II/genetics ; Plant Proteins/genetics ; Plant Proteins/metabolism ; Protein Kinase C-alpha/metabolism ; Proto-Oncogene Proteins c-myc/genetics ; eIF-2 Kinase/metabolism
Chemical Substances	I-kappa B Proteins ; MYC protein, human ; NF-kappa B ; Plant Proteins ; Proto-Oncogene Proteins c-myc ; Cyclin D1 (136601-57-5) ; Nitric Oxide Synthase Type II (EC 1.14.13.39) ; Cyclooxygenase 2 (EC 1.14.99.1) ; PTGS2 protein, human (EC 1.14.99.1) ; PERK kinase (EC 2.7.11.1) ; eIF-2 Kinase (EC 2.7.11.1) ; Protein Kinase C-alpha (EC 2.7.11.13)
Language	English
Publishing date	2009-12-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	205723-2
ISSN	1090-2104 ; 0006-291X ; 0006-291X
ISSN (online)	1090-2104 ; 0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2009.09.046
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Article ; Online: Increased β-catenin/Tcf signaling in pilocytic astrocytomas: a comparative study to distinguish pilocytic astrocytomas from low-grade diffuse astrocytomas.

Sareddy, Gangadhara Reddy / Geeviman, Khamushavalli / Panigrahi, Manas / Challa, Sundaram / Mahadevan, Anita / Babu, Phanithi Prakash

Neurochemical research

2011 Volume 37, Issue 1, Page(s) 96–104

Abstract: Although pilocytic and diffuse grade II astrocytomas considered as low-grade tumors, the distinction between them is still a major clinical problem. Previously we reported the activation of Wnt/β-catenin/Tcf signaling pathway in diffuse astrocytomas, ... ...

Abstract	Although pilocytic and diffuse grade II astrocytomas considered as low-grade tumors, the distinction between them is still a major clinical problem. Previously we reported the activation of Wnt/β-catenin/Tcf signaling pathway in diffuse astrocytomas, however its role in pilocytic astrocytomas is not well understood. In this study, we investigated the Wnt/β-catenin/Tcf pathway in pilocytic astrocytomas and compared with diffuse astrocytomas. We observed the differential expression of β-catenin, Tcf4, Lef1 and c-Myc in astrocytomas particularly higher levels were observed in pilocytic astrocytomas and GBM while very little expression was documented in grade II tumors. Further, immunohistochemical analysis revealed the strong positivity of β-catenin, Tcf4, Lef1 and c-Myc in pilocytic astrocytomas than that of grade II tumors and also exhibited the strong positivity in vascular endothelial cells of pilocytic astrocytomas and GBM. Hence, Wnt/β-catenin/Tcf signaling pathway is differentially expressed in astrocytomas, activation of this pathway might be helpful in separating pilocytic astrocytomas from low-grade diffuse astrocytomas.
MeSH term(s)	Adolescent ; Adult ; Astrocytoma/metabolism ; Astrocytoma/pathology ; Brain Neoplasms/metabolism ; Brain Neoplasms/pathology ; Child ; Child, Preschool ; Female ; Humans ; Immunohistochemistry ; Male ; Middle Aged ; Signal Transduction ; TCF Transcription Factors/metabolism ; beta Catenin/metabolism
Chemical Substances	TCF Transcription Factors ; beta Catenin
Language	English
Publishing date	2011-09-16
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	199335-5
ISSN	1573-6903 ; 0364-3190
ISSN (online)	1573-6903
ISSN	0364-3190
DOI	10.1007/s11064-011-0586-z
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Article ; Online: Estrogen receptor coregulator binding modulator (ERX-11) enhances the activity of CDK4/6 inhibitors against estrogen receptor-positive breast cancers.

Breast cancer research : BCR

2019 Volume 21, Issue 1, Page(s) 150

Abstract: Background: CDK4/6 inhibitors in combination with endocrine therapy (AE/AI/SERDs) are approved for the treatment of ER+ advanced breast cancer (BCa). However, not all patients benefit from CDK4/6 inhibitors therapy. We previously reported a novel ... ...

Abstract	Background: CDK4/6 inhibitors in combination with endocrine therapy (AE/AI/SERDs) are approved for the treatment of ER+ advanced breast cancer (BCa). However, not all patients benefit from CDK4/6 inhibitors therapy. We previously reported a novel therapeutic agent, ERX-11, that binds to the estrogen receptor (ER) and modulates ER-coregulator interactions. Here, we tested if the combination of ERX-11 with agents approved for ER+ BCa would be more potent. Methods: We tested the effect of combination therapy using BCa cell line models, including those that have acquired resistance to tamoxifen, letrozole, or CDK4/6 inhibitors or have been engineered to express mutant forms of the ER. In vitro activity was tested using Cell Titer-Glo, MTT, and apoptosis assays. Mechanistic studies were conducted using western blot, reporter gene assays, RT-qPCR, and mass spectrometry approaches. Xenograft, patient-derived explants (PDEs), and xenograft-derived explants (XDE) were used for preclinical evaluation and toxicity. Results: ERX-11 inhibited the proliferation of therapy-resistant BCa cells in a dose-dependent manner, including ribociclib resistance. The combination of ERX-11 and CDK4/6 inhibitor was synergistic in decreasing the proliferation of both endocrine therapy-sensitive and endocrine therapy-resistant BCa cells, in vitro, in xenograft models in vivo, xenograft-derived explants ex vivo, and in primary patient-derived explants ex vivo. Importantly, the combination caused xenograft tumor regression in vivo. Unbiased global mass spectrometry studies demonstrated profound decreases in proliferation markers with combination therapy and indicated global proteomic changes in E2F1, ER, and ER coregulators. Mechanistically, the combination of ERX-11 and CDK4/6 inhibitor decreased the interaction between ER and its coregulators, as evidenced by immunoprecipitation followed by mass spectrometry studies. Biochemical studies confirmed that the combination therapy significantly altered the expression of proteins involved in E2F1 and ER signaling, and this is primarily driven by a transcriptional shift, as noted in gene expression studies. Conclusions: Our results suggest that ERX-11 inhibited the proliferation of BCa cells resistant to both endocrine therapy and CDK4/6 inhibitors in a dose-dependent manner and that the combination of ERX-11 with a CDK4/6 inhibitor may represent a viable therapeutic approach.
MeSH term(s)	Animals ; Biomarkers, Tumor ; Breast Neoplasms/drug therapy ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cyclin-Dependent Kinase 4/antagonists & inhibitors ; Cyclin-Dependent Kinase 6/antagonists & inhibitors ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Drug Resistance, Neoplasm/genetics ; Drug Synergism ; Estrogen Receptor Modulators/pharmacology ; Female ; Humans ; Immunohistochemistry ; Mice ; Protein Kinase Inhibitors/pharmacology ; Receptors, Estrogen/metabolism
Chemical Substances	Biomarkers, Tumor ; Estrogen Receptor Modulators ; Protein Kinase Inhibitors ; Receptors, Estrogen ; CDK4 protein, human (EC 2.7.11.22) ; CDK6 protein, human (EC 2.7.11.22) ; Cyclin-Dependent Kinase 4 (EC 2.7.11.22) ; Cyclin-Dependent Kinase 6 (EC 2.7.11.22)
Language	English
Publishing date	2019-12-26
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2015059-3
ISSN	1465-542X ; 1465-5411
ISSN (online)	1465-542X
ISSN	1465-5411
DOI	10.1186/s13058-019-1227-8
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Zs.A 5494: Show issues

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Article ; Online: Estrogen receptor coregulator binding modulators (ERXs) effectively target estrogen receptor positive human breast cancers.

Raj, Ganesh V / Sareddy, Gangadhara Reddy / Ma, Shihong / Lee, Tae-Kyung / Viswanadhapalli, Suryavathi / Li, Rui / Liu, Xihui / Murakami, Shino / Chen, Chien-Cheng / Lee, Wan-Ru / Mann, Monica / Krishnan, Samaya Rajeshwari / Manandhar, Bikash / Gonugunta, Vijay K / Strand, Douglas / Tekmal, Rajeshwar Rao / Ahn, Jung-Mo / Vadlamudi, Ratna K

eLife

2017 Volume 6

Abstract: The majority of human breast cancer is estrogen receptor alpha (ER) positive. While anti-estrogens/aromatase inhibitors are initially effective, resistance to these drugs commonly develops. Therapy-resistant tumors often retain ER signaling, via ... ...

Abstract	The majority of human breast cancer is estrogen receptor alpha (ER) positive. While anti-estrogens/aromatase inhibitors are initially effective, resistance to these drugs commonly develops. Therapy-resistant tumors often retain ER signaling, via interaction with critical oncogenic coregulator proteins. To address these mechanisms of resistance, we have developed a novel ER coregulator binding modulator, ERX-11. ERX-11 interacts directly with ER and blocks the interaction between a subset of coregulators with both native and mutant forms of ER. ERX-11 effectively blocks ER-mediated oncogenic signaling and has potent anti-proliferative activity against therapy-sensitive and therapy-resistant human breast cancer cells. ERX-11 is orally bioavailable, with no overt signs of toxicity and potent activity in both murine xenograft and patient-derived breast tumor explant models. This first-in-class agent, with its novel mechanism of action of disrupting critical protein-protein interactions, overcomes the limitations of current therapies and may be clinically translatable for patients with therapy-sensitive and therapy-resistant breast cancers.
MeSH term(s)	Administration, Oral ; Animals ; Breast Neoplasms/drug therapy ; Cell Line, Tumor ; Disease Models, Animal ; Estrogen Receptor Antagonists/administration & dosage ; Estrogen Receptor Antagonists/metabolism ; Heterografts ; Humans ; Mice ; Neoplasm Transplantation ; Organ Culture Techniques ; Protein Binding ; Receptors, Estrogen/metabolism ; Signal Transduction/drug effects
Chemical Substances	Estrogen Receptor Antagonists ; Receptors, Estrogen
Language	English
Publishing date	2017-08-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.26857
Database	MEDical Literature Analysis and Retrieval System OnLINE

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