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Curcumin downregulates cell survival mechanisms in human prostate cancer cell lines

Abstract

While the role of nuclear transcription factor activator protein-1 (AP-1) in cell proliferation, and of nuclear factor-κB (NF-κB) in the suppression of apoptosis are known, their role in survival of prostate cancer cells is not well understood. We investigated the role of NF-κB and AP-1 in the survival of human androgen-independent (DU145) and -dependent (LNCaP) prostate cancer cell lines. Our results show that the faster rate of proliferation of DU145 cells when compared to LNCaP cells correlated with the constitutive expression of activated NF-κB and AP-1 in DU-145 cells. The lack of constitutive expression of NF-κB and AP-1 in LNCaP cells also correlated with their sensitivity to the antiproliferative effects of tumor necrosis factor (TNF). TNF induced NF-κB activation but not AP-1 activation in LNCaP cells. In DU145 cells both c-Fos and c-Jun were expressed and treatment with TNF activated c-Jun NH2-terminal kinase (JNK), needed for AP-1 activation. In LNCaP cells, however, only low levels of c-Jun was expressed and treatment with TNF minimally activated JNK. Treatment of cells with curcumin, a chemopreventive agent, suppressed both constitutive (DU145) and inducible (LNCaP) NF-κB activation, and potentiated TNF-induced apoptosis. Curcumin alone induced apoptosis in both cell types, which correlated with the downregulation of the expression of Bcl-2 and Bcl-xL and the activation of procaspase-3 and procaspase-8. Overall, our results suggest that NF-κB and AP-1 may play a role in the survival of prostate cancer cells, and curcumin abrogates their survival mechanisms.

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Abbreviations

AP-1:

activator protein-1

CHX:

cycloheximide

EMSA:

electrophoretic mobility shift assay

FBS:

fetal bovine serum

NF-κB:

nuclear transcription factor-κB

IκB:

inhibitory subunit of NF-κB

JNK:

c-jun N-terminal kinase

MTT:

[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide]

PARP:

poly (ADP-ribose) polymerase

PI:

propidium iodide

TNF:

tumor necrosis factor, SEAP, secretory alkaline phosphatase

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Acknowledgements

This research was conducted with support from The Clayton Foundation for Research.

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Correspondence to Bharat B Aggarwal.

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Mukhopadhyay, A., Bueso-Ramos, C., Chatterjee, D. et al. Curcumin downregulates cell survival mechanisms in human prostate cancer cell lines. Oncogene 20, 7597–7609 (2001). https://doi.org/10.1038/sj.onc.1204997

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