15-Deoxy-Δ12,14-prostaglandin J2 stabilizes hypoxia inducible factor-1α through induction of heme oxygenase-1 and direct modification ofprolyl-4-hydroxylase 2

Jee Eun Choi, Jung Hyun Kim, Na Young Song, Jinyoung Suh, Do Hee Kim, Su Jung Kim, Hye Kyung Na, Janos Nadas, Zigang Dong, Young Nam Cha, Young Joon Surh

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Abstract

15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), a representative J-series cyclopentenone prostaglandin, has biphasic roles in cell proliferation and apoptosis. Hypoxia inducible factor-1 (HIF-1) regulates expression of various genes involved in tumor growth and angiogenesis. In the present study, treatment of human breast cancer (MCF-7) cells with 15d-PGJ2 resulted in the accumulation of the α-subunit of HIF-1. Pretreatment with zinc protoporphyrin IX, a pharmacological inhibitor of heme oxygenase-1 (HO-1), as well as siRNA knockdown of HO-1 gene in MCF-7 cells attenuated 15d-PGJ2-mediated HIF-1α accumulation. 15d-PGJ2 treatment increased intracellular production of reactive oxygen species (ROS), which was mediated by HO-1 induction. Preincubation of MCF-7 cells with trolox, a water-soluble form of vitamin E, attenuated 15d-PGJ2-induced HIF-1α expression although HO-1 expression was unchanged. This finding suggests that ROS accumulated as a consequence of HO-1 up-regulation can enhance HIF-1α expression in MCF-7 cells treated with 15d-PGJ2. Alternatively, 15d-PGJ2 was found to covalently bind to HIF-1α prolyl-4-hydroxylase 2 (PHD2) in MCF-7 cells, which hampers the proline hydroxylation of HIF-1α, thereby disrupting ubiquitin-dependent proteasomal degradation of this transcription factor. Pretreatment with thiol reducing agents blunted 15d-PGJ2-induced HIF-1α stabilization, indicative of a cysteine residue as a direct target of 15d-PGJ2. Molecular docking analysis suggests that 15d-PGJ2 preferentially binds to PHD2 in the vicinity of the Cys201 residue based on binding energies and carbon–sulfur distances. In summary, 15d-PGJ2 stabilizes HIF-1α in MCF-7 cells through HO-1 induction with subsequent ROS generation and also through direct modification of PHD2.

Original languageEnglish (US)
Pages (from-to)1140-1152
Number of pages13
JournalFree Radical Research
Volume50
Issue number10
DOIs
StatePublished - Oct 2 2016

Keywords

  • 15-Deoxy-Δ-prostaglandin J
  • MCF-7 cells
  • cyclopentenone prostaglandin
  • heme oxygenase-1
  • hypoxia inducible factor-1α
  • prolyl-4-hydroxylase 2

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    Choi, J. E., Kim, J. H., Song, N. Y., Suh, J., Kim, D. H., Kim, S. J., Na, H. K., Nadas, J., Dong, Z., Cha, Y. N., & Surh, Y. J. (2016). 15-Deoxy-Δ12,14-prostaglandin J2 stabilizes hypoxia inducible factor-1α through induction of heme oxygenase-1 and direct modification ofprolyl-4-hydroxylase 2. Free Radical Research, 50(10), 1140-1152. https://doi.org/10.1080/10715762.2016.1219352