The mitochondrial ATP-dependent Lon protease: a novel target in lymphoma death mediated by the synthetic triterpenoid CDDO and its derivatives

Blood - Tập 119 Số 14 - Trang 3321-3329 - 2012
Steven H. Bernstein1, Sundararajan Venkatesh2, Min Li2, Jae Lee2, Bin Lü2, Shannon P. Hilchey1, Kimberly Morse1, Hollie M. Metcalfe1, Jolanta Skalska1, Michael Andreeff3, Paul S. Brookes4, Carolyn K. Suzuki2
1James P. Wilmot Cancer Center; University of Rochester Medical Center, Rochester, NY
2Department of Biochemistry and Molecular Biology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ;
3Molecular Hematology and Therapy, MD Anderson Cancer Center, Houston, TX; and
4Department of Anesthesiology, University of Rochester Medical Center, Rochester, NY

Tóm tắt

Abstract Synthetic triterpenoids are multitarget compounds exhibiting promise as preventative and therapeutic agents for cancer. Their proposed mechanism of action is by forming Michael adducts with reactive nucleophilic groups on target proteins. Our previous work demonstrates that the 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) and its derivatives promote B-lymphoid cell apoptosis through a mitochondria-mediated pathway linked to mitochondrial protein aggregation. As one function of the Lon protease is to eliminate abnormal mitochondrial proteins, we hypothesized that CDDO-induced protein aggregation and lymphoma apoptosis occur by inactivating this enzyme. Here, we show that CDDO and its derivatives directly and selectively inhibit Lon. CDDO blocks Lon-mediated proteolysis in biochemical and cellular assays, but does not inhibit the 20S proteasome. Furthermore, a biotinylated-CDDO conjugate modifies mitochondrial Lon. A striking common phenotype of CDDO-treated lymphoma cells and Lon-knockdown cells is the accumulation of electron-dense aggregates within mitochondria. We also show that Lon protein levels are substantially elevated in malignant lymphoma cells, compared with resting or activated B cells. Finally, we demonstrate that Lon knockdown leads to lymphoma cell death. Together, these findings suggest that Lon inhibition plays a contributory role in CDDO-induced lymphoma cell death, and support the concept that mitochondrial Lon is a novel anticancer drug target.

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Blood

Tập 119 Số 14

3321-3329

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