NQO1 suppresses NF-κB-p300 interaction to regulate inflammatory mediators associated with prostate tumorigenesis.

Abstract

NADPH reductase

NAD(P)H:

quinone oxidoreductase 1 (NQO1) is needed to maintain a cellular pool of antioxidants, and this enzyme may contribute to tumorigenesis on the basis of studies in NQO1-deficient mice. In this work, we sought deeper insights into how NQO1 contributes to prostate carcinogenesis, a setting in which oxidative stress and inflammation are established contributors to disease development and progression. In the TRAMP mouse model of prostate cancer, NQO1 was highly expressed in tumor cells. NQO1 silencing in prostate cancer cells increased levels of nuclear IKKα and NF-κB while decreasing the levels of p53, leading to interactions between NF-κB and p300 that reinforce survival signaling. Gene expression analysis revealed upregulation of a set of immune-associated transcripts associated with inflammation and tumorigenesis in cells in which NQO1 was attenuated, with IL8 confirmed functionally in cell culture as one key NQO1-supported cytokine. Notably, NQO1-silenced prostate cancer cells were more resistant to androgen deprivation. Furthermore, NQO1 inhibition increased migration, including under conditions of androgen deprivation. These results reveal a molecular link between NQO1 expression and proinflammatory cytokine signaling in prostate cancer. Furthermore, our results suggest that altering redox homeostasis through NQO1 inhibition might promote androgen-independent cell survival via opposing effects on NF-κB and p53 function.

• Authors: Dinesh Thapa, Peng Meng, Roble G Bedolla, Robert L Reddick, Addanki P Kumar, Rita Ghosh
• Journal: Cancer research (Cancer Res) Vol. 74 Issue 19 Pg. 5644-55 (Oct 01 2014) ISSN: 1538-7445 [Electronic] United States
• PMID: 25125658 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Inflammation Mediators
• Interleukin-8
• NF-kappa B
• Tumor Suppressor Protein p53
• NAD(P)H Dehydrogenase (Quinone)
• NQO1 protein, human
• p300-CBP Transcription Factors

Topics

• Carcinogenesis
• Cell Line, Tumor
• Gene Knockdown Techniques
• Humans
• Inflammation Mediators (physiology)
• Interleukin-8 (biosynthesis)
• Male
• NAD(P)H Dehydrogenase (Quinone) (genetics, physiology)
• NF-kappa B (metabolism)
• Prostatic Neoplasms (pathology, physiopathology)
• Protein Binding
• Real-Time Polymerase Chain Reaction
• Tumor Suppressor Protein p53 (metabolism)
• p300-CBP Transcription Factors (metabolism)