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Heme Oxygenase-1 Influences Apoptosis via CO-mediated Inhibition of K+ Channels

  • Moza M. Al-Owais
  • Mark L. Dallas
  • John P. Boyle
  • Jason L. Scragg
  • Chris PeersEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 860)

Abstract

Hypoxic/ischemic episodes can trigger oxidative stress-mediated loss of central neurons via apoptosis, and low pO2 is also a feature of the tumor microenvironment, where cancer cells are particularly resistant to apoptosis. In the CNS, ischemic insult increases expression of the CO-generating enzyme heme oxygenase-1 (HO-1), which is commonly constitutively active in cancer cells. It has been proposed that apoptosis can be regulated by the trafficking and activity of K+ channels, particularly Kv2.1. We have explored the idea that HO-1 may influence apoptosis via regulation of Kv2.1. Overexpression of Kv2.1 in HEK293 cells increased their vulnerability to oxidant-induced apoptosis. CO (applied as the donor CORM-2) protected cells against apoptosis and inhibited Kv2.1 channels. Similarly in hippocampal neurones, CO selectively inhibited Kv2.1 and protected neurones against oxidant-induced apoptosis. In medulloblastoma sections we identified constitutive expression of HO-1 and Kv2.1, and in the medulloblastoma-derived cell line DAOY, hypoxic HO-1 induction or exposure to CO protected cells against apoptosis, and also selectively inhibited Kv2.1 channels expressed in these cells. These studies are consistent with a central role for Kv2.1 in apoptosis in both central neurones and cancer cells. They also suggest that HO-1 expression can strongly influence apoptosis via CO-mediated regulation of Kv2.1 activity.

Keywords

Heme oxygenase Carbon monoxide Kv2.1 K+ channel Neurone Medulloblastoma Apoptosis 

Notes

Acknowledgements

This work was supported by the Yorkshire Cancer Research and The Wellcome Trust.

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Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Moza M. Al-Owais
    • 1
  • Mark L. Dallas
    • 2
  • John P. Boyle
    • 1
  • Jason L. Scragg
    • 1
  • Chris Peers
    • 1
    Email author
  1. 1.Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and HealthUniversity of LeedsLeedsUK
  2. 2.School of PharmacyUniversity of ReadingReadingUK

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