HIF-1 and NF-kappaB-mediated upregulation of CXCR1 and CXCR2 expression promotes cell survival in hypoxic prostate cancer cells

Pamela Maxwell, Rebecca Gallagher, I.J. Stratford, Angela Seaton, Catherine Wilson, Paula Scullin, [No Value] Messenger, K.J. Williams, Patrick Johnston, David Waugh

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158 Citations (Scopus)

Abstract

Hypoxic cancer cells are resistant to treatment, leading to the selection of cells with a more malignant phenotype. The expression of interleukin-8 (IL-8) plays an important role in the tumorigenesis and metastasis of solid tumors including prostate cancer. Recently, we detected elevated expression of IL-8 and IL-8 receptors in human prostate cancer tissue. The objective of the current study was to determine whether hypoxia increases IL-8 and IL-8 receptor expression in prostate cancer cells and whether this contributes to a survival advantage in hypoxic cells. IL-8, CXCR1 and CXCR2 messenger RNA (mRNA) expression in PC3 cells was upregulated in response to hypoxia in a time-dependent manner. Elevated IL-8 secretion following hypoxia was detected by enzyme-linked immunosorbent assay, while immunoblotting confirmed elevated receptor expression. Attenuation of hypoxia-inducible factor (HIF-1) and nuclear factor-kappaB (NF-kappaB) transcriptional activity using small interfering RNA (siRNA), a HIF-1 dominant-negative and pharmacological inhibitors, abrogated hypoxia-induced transcription of CXCR1 and CXCR2 in PC3 cells. Furthermore, chromatin-IP analysis demonstrated binding of HIF-1 and NF-kappaB to CXCR1. Finally, inhibition of IL-8 signaling potentiated etoposide-induced cell death in hypoxic PC3 cells. These results suggest that IL-8 signaling confers a survival advantage to hypoxic prostate cancer cells, and therefore, strategies to inhibit IL-8 signaling may sensitize hypoxic tumor cells to conventional treatments.
Original languageEnglish
Pages (from-to)7333-7345
Number of pages13
JournalOncogene
Volume26
Issue number52
DOIs
Publication statusPublished - 15 May 2007

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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    Maxwell, P., Gallagher, R., Stratford, I. J., Seaton, A., Wilson, C., Scullin, P., Messenger, N. V., Williams, K. J., Johnston, P., & Waugh, D. (2007). HIF-1 and NF-kappaB-mediated upregulation of CXCR1 and CXCR2 expression promotes cell survival in hypoxic prostate cancer cells. Oncogene, 26(52), 7333-7345. https://doi.org/10.1038/sj.onc.1210536