XPC silencing in normal human keratinocytes triggers metabolic alterations through NOX-1 activation-mediated reactive oxygen species

Biochim Biophys Acta. 2011 Jun;1807(6):609-19. doi: 10.1016/j.bbabio.2010.12.006. Epub 2010 Dec 15.

Abstract

Cancer cells utilize complex mechanisms to remodel their bioenergetic properties. We exploited the intrinsic genomic stability of xeroderma pigmentosum C (XPC) to understand the inter-relationships between genomic instability, reactive oxygen species (ROS) generation, and metabolic alterations during neoplastic transformation. We showed that knockdown of XPC (XPC(KD)) in normal human keratinocytes results in metabolism remodeling through NADPH oxidase-1 (NOX-1) activation, which in turn leads to increased ROS levels. While enforcing antioxidant defenses by overexpressing catalase, CuZnSOD, or MnSOD could not block the metabolism remodeling, impaired NOX-1 activation abrogates both alteration in ROS levels and modifications of energy metabolism. As NOX-1 activation is observed in human squamous cell carcinomas (SCCs), the blockade of NOX-1 could be a target for the prevention and the treatment of skin cancers.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antioxidants / metabolism
  • Base Sequence
  • Cells, Cultured
  • DNA-Binding Proteins / antagonists & inhibitors*
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Humans
  • Keratinocytes / drug effects
  • Keratinocytes / metabolism*
  • Keratinocytes / physiology
  • Metabolic Networks and Pathways / drug effects
  • Metabolic Networks and Pathways / genetics
  • Models, Biological
  • Molecular Sequence Data
  • NADPH Oxidase 1
  • NADPH Oxidases / metabolism*
  • NADPH Oxidases / physiology
  • Oxidative Stress / drug effects
  • Oxidative Stress / genetics
  • Oxidative Stress / physiology
  • RNA Interference* / drug effects
  • RNA Interference* / physiology
  • RNA, Small Interfering / pharmacology
  • Reactive Oxygen Species / adverse effects*
  • Reactive Oxygen Species / metabolism
  • Sequence Homology, Nucleic Acid

Substances

  • Antioxidants
  • DNA-Binding Proteins
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • XPC protein, human
  • NADPH Oxidase 1
  • NADPH Oxidases
  • NOX1 protein, human