Oral communication, iL44

Official XXIst International Pigment Cell Conference website - 21-24 Sept 2011, Bordeaux - France | updated: September 04 2011

Xeroderma pigmentosum: clues to understand cancer initiation

SPEAKER H.R. Rezvani #whois submiter ?
AUTHOR(s) H.R. Rezvani

The works developed in the last decades on patients and cells of rare disorders of photoprotection indicates that these are very useful models to understand complex diseases such as cancer. As DNA damage and metabolism remodeling are two well-known hallmarks of cancer cells, we took advantage of the intrinsic genomic instability arising in type C xeroderma pigmentosum (XPC) to understand the inter-relationships between these two factors. We showed that lentivirus-mediated knockdown of XPC (XPCKD) in keratinocytes reduces mitochondrial oxidative phosphorylation and increases glycolysis, a hallmark observed in most cancer cells as shown by PET scans in the clinic. The critical step in this process is the activation of bypass repair systems which helps cells with unrepaired DNA escape senescence and death. In fact, activation of DNA-dependent protein kinase results in upregulation of AKT and NADPH oxidase-1 (NOX1) with a concomitant increase in reactive oxygen species (ROS) production, associated with specific deletions in mitochondrial DNA (mtDNA). The XPCKD containing mtDNA deletions are capable of forming squamous cell carcinomas (SCCs) when implanted into immunodeficient mice. Impairment of AKT or NOX activation in XPCKD cells blocks the formation of ROS, mtDNA deletions, and neoplastic transformation. The knowledge gained by studying XPC silencing-mediated tumoral transformation of normal human keratinocytes has given us a greater insight into the contribution of metabolism alteration and ROS accumulation to skin cancer. Further elucidation of the molecular mechanisms involved in skin cancer formation may ultimately lead to implement new strategies for the prevention of skin but of also of other cancers.



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Université de Bordeaux 2 & Conseil Régional Aquitaine