Inhibition of the Mitochondrial Protease ClpP as a Therapeutic Strategy for Human Acute Myeloid Leukemia

Abstract

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 the leukemic cells from approximately half of 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 ClpP interacts with mitochondrial respiratory chain proteins and metabolic enzymes, and knockdown of ClpP in leukemic cells inhibited oxidative phosphorylation and mitochondrial metabolism.

Syntaphilin controls a mitochondrial rheostat for proliferation-motility decisions in cancer

“…One possibility is that SNPH operates in concert with other regulators of complex II (39), including survivin (26), to preserve subunit assembly and optimal bioenergetics, especially under stress conditions. In fact, it is intriguing that compared with other mitochondrial respiration complexes, complex II appears especially vulnerable to stress stimuli, including defective mitochondrial protein folding (40)(41)(42) and oxidative damage (the present study).…”

Cancer cells exploit adaptive mitochondrial dynamics to increase tumor cell invasion

“…9 Mechanistic aspects of how tumors may regulate oxidative phosphorylation have also come into better focus, with a key role of protein folding quality control maintained by mitochondria-localized Heat Shock Protein-90 (mtHsp90) chaperones, 49 as well as organelle proteases, 50 in ensuring the stability and function of respiratory protein complexes.…”

Antagonizing ClpP: A New Power Play in Targeted Therapy for AML

“…The lack of progress in AML has prompted pursuit of both hypotheses among AML investigators. In this issue of Cancer Cell, Cole et al (2015) provide new hope that a more universal target indeed exists in this disease.…”

“…This compound's anti-leukemic activity is due to inhibition of mitochondrial translation (Skrti c et al, 2011). Based on this observation, Cole et al (2015) looked to identify which mitochondrial proteins were critical to proliferation using a small hairpin RNA (shRNA) screen with an AML cell line and found caseinolytic protease (ClpP) to be necessary for cell survival, whereas other mitochondrial proteases were not. ClpP is a serine protease that was first identified in bacteria, where it garnered interest as a potential target for anti-microbial therapy (Zeiler et al, 2012).…”

“…In mammals, ClpP is encoded by a nuclear gene, and the translated protein is transported into the mitochondria and localized to the inner membrane where it degrades mitochondrial proteins damaged by oxidative stress ( Figure 1A) (Corydon et al, 1998). Cole et al (2015) began with the discovery that ClpP was overexpressed in 45% of 511 primary AML samples, irrespective of cytogenetics or mutational status, compared to CD34 + cells from 21 healthy controls. The authors hypothesized that CLPP overexpression may be the result of increased mitochondrial stress, an end-result of several possible pathways that obviates any correlation with a known genomic subtype of the disease.…”