Inhibition of DNA-Dependent Protein Kinase Activity for Breast Cancer Therapy
Abstract
The formation of DNA double strand breaks (DSBs) correlates well with lethality of cancer cells following ionizing radiation (IR) . The DNA-dependent protein kinase (DNA-PK) complex is a major factor in the repair of DSBs in mammalian cells. It is composed of a catalytic subunit (DNA-PKcs) and a DNA end binding subunit (the Ku7O/Ku8O heterodimer). Given Ku7O knock-out mice show both hypersensitive to IR and growth retardation, Ku70 are involved in DNA repair and cell growth. Blocking Ku7O function can have dual impacts on cancer cells: to sensitize cancer cells to DNA damage agents, such as ionizing radiation and chemotheraputic drugs, while suppress cancer cell growth. We confirmed Ku70-Hsp90 interaction in yeast and human breast cancer cells, and is needed for Hsp90 stability. Hsp90 is a molecular chaperone, and its client proteins are typically involved in signal transduction (Akt), cell cycle control. Ku7O antisense oligo treatment lowers protein levels in both Hsp9O and Akt similar to Hsp9O inhibitors suggesting Akt signal pathway is the downstream of Ku70-Hsp90 interaction for cell growth. Overall, the research supported by this grant not only lead to better understanding of Ku70-Hsp90 related-cell growth pathway, but also to identify Ku70-Hsp90 as a new target for cancer therapy.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2002
- Accession Number
- ADB283924
Entities
People
- Yang Chin-rang
Organizations
- University of Rochester