Discovery may lead to development of new, more effective targeted cancer therapies

-- Jeff Muise

Friday, August 27, 2010 (Last Updated: 08/31/2010)

FRIDAY, Aug. 27 (HealthDay News) -- Researchers have discovered a mechanism by which adenoviruses breach cellular defenses, and this could help explain how p53 tumor-suppressor genes are disabled in cancer cells and point the way to the development of new, more effective targeted cancer therapies; these findings have been published in the Aug. 26 issue of Nature.

Conrado Soria, Ph.D., of the Salk Institute for Biological Studies in La Jolla, Calif., and colleagues cultured human cells, infected them with adenoviruses, and then studied the resulting biochemical processes and proteins produced in the suppression of transcription factor p53, a cell defense mechanism that is disabled in almost all cancers.

In adenovirus infection, the viral protein E1B-55K binds to and degrades p53 in infected cells so the virus can reproduce. Current oncolytic targeted cancer therapies utilize E1B-55K-deficient adenoviruses to target and kill cancer cells, in which p53 has been disabled by the cancer. However, the researchers discovered another adenoviral protein, E4-ORF3, which prevents p53 from binding to its target genes by modifying chromatin to bury the regulatory regions in dense heterochromatin. The researchers said this new insight also might explain how p53 is disabled in cancer cells and could provide insights into the potential development of true p53-selective oncolytic viral therapies.

"Finally, our identification of E4-ORF3 changes the fundamental definition of how p53 is inactivated in adenovirus-infected cells, which is a critical mechanistic insight that could now enable the rational development of true p53 tumor-selective adenoviral therapies," the authors write.

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