Glioblastoma multiforme (GBM) is an almost uniformly fatal brain cancer. The current treatment for GBM is radiation with oral chemotherapy. GBM patients treated with chemotherapy and radiation have life expectancies of only 14 months. These statistics make it obvious that better treatment approaches are needed to improve the effectiveness of radiation for GBM. Radiation causes DNA damage which activates signaling pathways that are thought to improve the ability of cells to repair DNA damage. The damage sensing pathways that are triggered by radiation, for the most part, are dependent on protein phosphorylation (adding a phosphate group to proteins). Protein phosphorylation reflects the balance between two opposing sets of enzymes: kinases that add a phosphate group to proteins and phosphatases that remove a phosphate group from proteins. Drugs that block kinases have already been successfully used to improve the clinical effectiveness of radiation therapy. For example, advanced-stage head and neck cancers are treated with radiation in addition to a drug that blocks kinases. At this time, however, protein phosphatases have received little attention but have the potential to make radiation more effective. We have discovered a specific role for a newly discovered protein phosphatase called phosphatase-6 (PP6) which plays a critical role in regulating a key DNA repair protein called DNA-PK. Depletion of PP6 dramatically sensitizes glioblastoma cells to radiation. Our long term goal is to make glioblastoma cells more sensitive to radiation through the use of drugs that block PP6's ability to activate DNA-PK. However, before such drugs can be used, it is necessary to define the molecular mechanisms by which PP6 regulates DNA-PK following radiation.
Despite optimal treatment (radiation and oral chemotherapy), patients diagnosed with the fatal brain cancer Glioblastoma multiforme (GBM) have life expectancies of only 14 months. This statistic makes it obvious that novel approaches are necessary to improve the effectiveness of radiation for GBM patients. Our goal is to develop a drug that will enhance the effectiveness of radiation for patients and thereby improve the prognosis of GBM patients.
|Sarkar, S; Brautigan, D L; Parsons, S J et al. (2014) Androgen receptor degradation by the E3 ligase CHIP modulates mitotic arrest in prostate cancer cells. Oncogene 33:26-33|
|Ohama, Takashi; Wang, Lifu; Griner, Erin M et al. (2013) Protein Ser/Thr phosphatase-6 is required for maintenance of E-cadherin at adherens junctions. BMC Cell Biol 14:42|
|Eto, Masumi; Brautigan, David L (2012) Endogenous inhibitor proteins that connect Ser/Thr kinases and phosphatases in cell signaling. IUBMB Life 64:732-9|
|Holy, Maja; Brautigan, David L (2012) Calyculin A from Discodermia calyx is a dual action toxin that blocks calcium influx and inhibits protein Ser/Thr phosphatases. Toxins (Basel) 4:940-54|
|Hosing, Amol S; Valerie, Nicholas C K; Dziegielewski, Jaroslaw et al. (2012) PP6 regulatory subunit R1 is bidentate anchor for targeting protein phosphatase-6 to DNA-dependent protein kinase. J Biol Chem 287:9230-9|
|Edelson, Jessica R; Brautigan, David L (2011) The Discodermia calyx toxin calyculin a enhances cyclin D1 phosphorylation and degradation, and arrests cell cycle progression in human breast cancer cells. Toxins (Basel) 3:105-19|