Suppressing TRAP-1 protein led to prostate cancer cell death and did not affect noncancerous cells, as reported in AJP.
Inhibiting TNF-receptor associated protein-1 (TRAP-1) may prevent cancer cell death, according to investigators at the University of Massachusetts Medical School. They also note that TRAP-1 is a marker of localized and metastatic prostate cancer and is required for prostate cancer cell viability.
The report will appear in the January 2010 issue of the American Journal of Pathology in a paper titled “Cytoprotective Mitochondrial Chaperone TRAP-1 as a Novel Molecular Target in Localized and Metastatic Prostate Cancer.”
Since TRAP-1 is known to regulate cell death, the researchers decided to study its role in prostate cancer. They found that the protein was highly expressed in both high-grade human prostate cancer lesions and mouse models of prostate cancer but not in benign or normal prostate tissue.
In addition, TRAP-1 overexpression in noncancer prostate cells inhibited cell death, whereas TRAP-1-deficient prostate cancer cells had enhanced levels of cell death. Moreover, treatment with gamitrinibs, a class of small molecules that inhibit TRAP-1, resulted in prostate cancer cell death but not death of noncancerous prostate cells.
Dario C. Altieri, M.D., who led this research, reported in February on the synthesis and properties of gamitrinib as a treatment for prostate cancer in The Journal of Clinical Investigation. He designed gamitrinibs to selectively target Hsp90 in human tumor mitochondria. TRAP-1 is a mitochondria-localized Hsp90 chaperone. Therefore, Dr. Altieri believes that based on his research, targeting TRAP-1 via gamitrinib may be a viable therapeutic strategy for patients with advanced prostate cancer.
Dr. Altieri’s experiments also found that TRAP-1 was differentially expressed in localized and metastatic prostate cancer compared with normal prostate.
A similar approach may be also suitable for other types of cancer, as TRAP-1 is broadly expressed in disparate human malignancies, Dr. Altieri continues. He plans to “further dissect the biology of TRAP-1 cytoprotection in cancer cells and test whether disabling its function may overcome drug resistance, the most common reason of treatment failure and dismal outcome in patients with advanced prostate cancer.”