Effects of IKK inhibitor PS1145 on NF-κB function, proliferation, apoptosis and invasion activity in prostate carcinoma cells

A. Yemelyanov; A. Gasparian; P. Lindholm; L. Dang; J. W. Pierce; F. Kisseljov; A. Karseladze; I. Budunova

doi:10.1038/sj.onc.1209066

Effects of IKK inhibitor PS1145 on NF-κB function, proliferation, apoptosis and invasion activity in prostate carcinoma cells

A. Yemelyanov, A. Gasparian, P. Lindholm, L. Dang, J. W. Pierce, F. Kisseljov, A. Karseladze, I. Budunova^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

112 Scopus citations

Abstract

A key antiapoptotic transcription factor, nuclear factor kappa-B (NF-κB), is known to be critically important for tumor cell growth, angiogenesis and development of metastatic lesions. We and others showed previously that NF-κB transcription factor was constitutively activated in androgen-independent prostate carcinoma (PC) cell lines due to the upregulated activity of inhibitor of NF-κB kinases (IKK). In this work, using luciferase assay, electrophoretic mobility shift assay and Northern blot analysis of expression of endogenous κB-responsive genes, we demonstrate that a novel highly specific small-molecule IKK inhibitor, PS1145, efficiently inhibited both basal and induced NF-κB activity in PC cells. We found that PS1145 induced caspase 3/7-dependent apoptosis in PC cells and significantly sensitized PC cells to apoptosis induced by tumor necrosis factor alpha. We also showed that PS1145 inhibited PC cell proliferation. Effects of PS1145 on proliferation and apoptosis correlated with inhibition of interleukin (IL)-6, cyclin D1, D2, inhibitor of apoptosis (IAP)-1 and IAP-2 gene expression and decreased IL-6 protein level. In addition, we found that incubation with PS1145 inhibited the invasion activity of highly invasive PC3-S cells in invasion chamber assay in a dose-dependent manner. Overall, this study provides the framework for development of a novel therapeutic approach targeting NF-κB transcription factor to treat advanced PC.

Original language	English (US)
Pages (from-to)	387-398
Number of pages	12
Journal	Oncogene
Volume	25
Issue number	3
DOIs	https://doi.org/10.1038/sj.onc.1209066
State	Published - Jan 19 2006

Funding

We thank Dr WC Greene (Gladstone Institute for Virology and Immunology, University of California, San Francisco, CA, USA) and Dr F Mercurio (Signal Pharmaceutical, Inc., San Diego, CA, USA) for their kind gift of plasmids. This work was supported by DOD prostate grants DAMD17-01-1-0015 and DAMD17-03-1-0522 (to IB), Northwestern University Prostate SPORE Developmental Project (to IB), and Russian Foundation for Basic Research, grant # 0404-49240a (to AG).

Keywords

Apoptosis
IKK
Invasion
NF-κB
Prostate carcinoma

ASJC Scopus subject areas

Molecular Biology
Genetics
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/sj.onc.1209066

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@article{458c0eb045f44edb9a753733ce5fe143,

title = "Effects of IKK inhibitor PS1145 on NF-κB function, proliferation, apoptosis and invasion activity in prostate carcinoma cells",

abstract = "A key antiapoptotic transcription factor, nuclear factor kappa-B (NF-κB), is known to be critically important for tumor cell growth, angiogenesis and development of metastatic lesions. We and others showed previously that NF-κB transcription factor was constitutively activated in androgen-independent prostate carcinoma (PC) cell lines due to the upregulated activity of inhibitor of NF-κB kinases (IKK). In this work, using luciferase assay, electrophoretic mobility shift assay and Northern blot analysis of expression of endogenous κB-responsive genes, we demonstrate that a novel highly specific small-molecule IKK inhibitor, PS1145, efficiently inhibited both basal and induced NF-κB activity in PC cells. We found that PS1145 induced caspase 3/7-dependent apoptosis in PC cells and significantly sensitized PC cells to apoptosis induced by tumor necrosis factor alpha. We also showed that PS1145 inhibited PC cell proliferation. Effects of PS1145 on proliferation and apoptosis correlated with inhibition of interleukin (IL)-6, cyclin D1, D2, inhibitor of apoptosis (IAP)-1 and IAP-2 gene expression and decreased IL-6 protein level. In addition, we found that incubation with PS1145 inhibited the invasion activity of highly invasive PC3-S cells in invasion chamber assay in a dose-dependent manner. Overall, this study provides the framework for development of a novel therapeutic approach targeting NF-κB transcription factor to treat advanced PC.",

keywords = "Apoptosis, IKK, Invasion, NF-κB, Prostate carcinoma",

author = "A. Yemelyanov and A. Gasparian and P. Lindholm and L. Dang and Pierce, {J. W.} and F. Kisseljov and A. Karseladze and I. Budunova",

note = "Funding Information: We thank Dr WC Greene (Gladstone Institute for Virology and Immunology, University of California, San Francisco, CA, USA) and Dr F Mercurio (Signal Pharmaceutical, Inc., San Diego, CA, USA) for their kind gift of plasmids. This work was supported by DOD prostate grants DAMD17-01-1-0015 and DAMD17-03-1-0522 (to IB), Northwestern University Prostate SPORE Developmental Project (to IB), and Russian Foundation for Basic Research, grant # 0404-49240a (to AG).",

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doi = "10.1038/sj.onc.1209066",

language = "English (US)",

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T1 - Effects of IKK inhibitor PS1145 on NF-κB function, proliferation, apoptosis and invasion activity in prostate carcinoma cells

AU - Yemelyanov, A.

AU - Gasparian, A.

AU - Lindholm, P.

AU - Dang, L.

AU - Pierce, J. W.

AU - Kisseljov, F.

AU - Karseladze, A.

AU - Budunova, I.

N1 - Funding Information: We thank Dr WC Greene (Gladstone Institute for Virology and Immunology, University of California, San Francisco, CA, USA) and Dr F Mercurio (Signal Pharmaceutical, Inc., San Diego, CA, USA) for their kind gift of plasmids. This work was supported by DOD prostate grants DAMD17-01-1-0015 and DAMD17-03-1-0522 (to IB), Northwestern University Prostate SPORE Developmental Project (to IB), and Russian Foundation for Basic Research, grant # 0404-49240a (to AG).

PY - 2006/1/19

Y1 - 2006/1/19

N2 - A key antiapoptotic transcription factor, nuclear factor kappa-B (NF-κB), is known to be critically important for tumor cell growth, angiogenesis and development of metastatic lesions. We and others showed previously that NF-κB transcription factor was constitutively activated in androgen-independent prostate carcinoma (PC) cell lines due to the upregulated activity of inhibitor of NF-κB kinases (IKK). In this work, using luciferase assay, electrophoretic mobility shift assay and Northern blot analysis of expression of endogenous κB-responsive genes, we demonstrate that a novel highly specific small-molecule IKK inhibitor, PS1145, efficiently inhibited both basal and induced NF-κB activity in PC cells. We found that PS1145 induced caspase 3/7-dependent apoptosis in PC cells and significantly sensitized PC cells to apoptosis induced by tumor necrosis factor alpha. We also showed that PS1145 inhibited PC cell proliferation. Effects of PS1145 on proliferation and apoptosis correlated with inhibition of interleukin (IL)-6, cyclin D1, D2, inhibitor of apoptosis (IAP)-1 and IAP-2 gene expression and decreased IL-6 protein level. In addition, we found that incubation with PS1145 inhibited the invasion activity of highly invasive PC3-S cells in invasion chamber assay in a dose-dependent manner. Overall, this study provides the framework for development of a novel therapeutic approach targeting NF-κB transcription factor to treat advanced PC.

AB - A key antiapoptotic transcription factor, nuclear factor kappa-B (NF-κB), is known to be critically important for tumor cell growth, angiogenesis and development of metastatic lesions. We and others showed previously that NF-κB transcription factor was constitutively activated in androgen-independent prostate carcinoma (PC) cell lines due to the upregulated activity of inhibitor of NF-κB kinases (IKK). In this work, using luciferase assay, electrophoretic mobility shift assay and Northern blot analysis of expression of endogenous κB-responsive genes, we demonstrate that a novel highly specific small-molecule IKK inhibitor, PS1145, efficiently inhibited both basal and induced NF-κB activity in PC cells. We found that PS1145 induced caspase 3/7-dependent apoptosis in PC cells and significantly sensitized PC cells to apoptosis induced by tumor necrosis factor alpha. We also showed that PS1145 inhibited PC cell proliferation. Effects of PS1145 on proliferation and apoptosis correlated with inhibition of interleukin (IL)-6, cyclin D1, D2, inhibitor of apoptosis (IAP)-1 and IAP-2 gene expression and decreased IL-6 protein level. In addition, we found that incubation with PS1145 inhibited the invasion activity of highly invasive PC3-S cells in invasion chamber assay in a dose-dependent manner. Overall, this study provides the framework for development of a novel therapeutic approach targeting NF-κB transcription factor to treat advanced PC.

KW - Apoptosis

KW - IKK

KW - Invasion

KW - NF-κB

KW - Prostate carcinoma

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ER -

Effects of IKK inhibitor PS1145 on NF-κB function, proliferation, apoptosis and invasion activity in prostate carcinoma cells

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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