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

Oncogene volume 25, pages 387–398 (2006)Cite this article

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.

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Abbreviations

EMSA:

electrophoretic mobility shift assay

Erk:

extracellular signal-regulated kinase

IAP:

inhibitor of apoptosis

IKK:

inhibitor of nuclear factor kappa-B kinase

IκB:

inhibitor of nuclear factor kappa-B

IL:

interleukin

LPS:

lipopolysaccharide

MAPK:

mitogen-activated protein kinase

Mek1/2:

dual-specificity mitogen-activated protein kinase kinase 1

NF-κB:

nuclear factor kappa-B

PC:

prostate carcinoma

SAPK/JNK:

stress-activated protein kinase/Jun-N-terminal kinase

TNF-α:

tumor necrosis factor alpha

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Acknowledgements

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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  1. J W Pierce

    Present address: Merck Research Laboratories Boston, Boston, MA, USA

  2. A Yemelyanov and A Gasparian: These two authors contributed equally to this work.

Authors and Affiliations

  1. Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    A Yemelyanov, P Lindholm & I Budunova

  2. NN Blokhin Russian Cancer Research Center, Moscow, Russia

    A Gasparian, F Kisseljov & A Karseladze

  3. Millennium Pharmaceuticals Inc., Cambridge, MA, USA

    L Dang & J W Pierce

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  1. A Yemelyanov
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Correspondence to I Budunova.

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Yemelyanov, A., Gasparian, A., Lindholm, P. et al. Effects of IKK inhibitor PS1145 on NF-κB function, proliferation, apoptosis and invasion activity in prostate carcinoma cells. Oncogene 25, 387–398 (2006). https://doi.org/10.1038/sj.onc.1209066

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