[PDF][PDF] Inhibition of the mitochondrial protease ClpP as a therapeutic strategy for human acute myeloid leukemia

A Cole, Z Wang, E Coyaud, V Voisin, M Gronda… - Cancer cell, 2015 - cell.com
A Cole, Z Wang, E Coyaud, V Voisin, M Gronda, Y Jitkova, R Mattson, R Hurren, S Babovic…
Cancer cell, 2015cell.com
From an shRNA screen, we identified ClpP as a member of the mitochondrial proteome
whose knockdown reduced the viability of K562 leukemic cells. Expression of this
mitochondrial protease that has structural similarity to the cytoplasmic proteosome is
increased in leukemic cells from approximately half of all patients with AML. Genetic or
chemical inhibition of ClpP killed cells from both human AML cell lines and primary samples
in which the cells showed elevated ClpP expression but did not affect their normal …
Summary
From an shRNA screen, we identified ClpP as a member of the mitochondrial proteome whose knockdown reduced the viability of K562 leukemic cells. Expression of this mitochondrial protease that has structural similarity to the cytoplasmic proteosome is increased in leukemic cells from approximately half of all patients with AML. Genetic or chemical inhibition of ClpP killed cells from both human AML cell lines and primary samples in which the cells showed elevated ClpP expression but did not affect their normal counterparts. Importantly, Clpp knockout mice were viable with normal hematopoiesis. Mechanistically, we found that ClpP interacts with mitochondrial respiratory chain proteins and metabolic enzymes, and knockdown of ClpP in leukemic cells inhibited oxidative phosphorylation and mitochondrial metabolism.
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