Characterization of TR‐107, a novel chemical activator of the human mitochondrial protease ClpP

Abstract

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Targeting Mitochondria with ClpP Agonists as a Novel Therapeutic Opportunity in Breast Cancer

“…CLPP is an essential gene for cell survival in leukemia cells and ClpP inhibition is lethal in acute myelogenous leukemia (AML), chronic myelogenous leukemia, and osteosarcoma [ 262 ]. In contrast, ClpP activators show anti-tumor effect in breast, ovary, colorectal, glioblastoma, and other cancers [ 58 , 268 , 269 , 270 , 271 , 272 ]. In breast cancer cells, transient knockdown of CLPP by siRNA induced apoptosis and inhibited cell viability, migration, invasion in breast cancer cells [ 265 ], while CRISPR/Cas9-mediated deletion of CLPP gene did not affect cell viability presumably due to cellular adaptation [ 58 , 270 ].…”

“…In contrast, ClpP activators show anti-tumor effect in breast, ovary, colorectal, glioblastoma, and other cancers [ 58 , 268 , 269 , 270 , 271 , 272 ]. In breast cancer cells, transient knockdown of CLPP by siRNA induced apoptosis and inhibited cell viability, migration, invasion in breast cancer cells [ 265 ], while CRISPR/Cas9-mediated deletion of CLPP gene did not affect cell viability presumably due to cellular adaptation [ 58 , 270 ]. In contrast, activation of ClpP by ClpP agonists exerts an anti-tumor effect in breast cancer cells [ 58 , 270 ].…”

“…In breast cancer cells, transient knockdown of CLPP by siRNA induced apoptosis and inhibited cell viability, migration, invasion in breast cancer cells [ 265 ], while CRISPR/Cas9-mediated deletion of CLPP gene did not affect cell viability presumably due to cellular adaptation [ 58 , 270 ]. In contrast, activation of ClpP by ClpP agonists exerts an anti-tumor effect in breast cancer cells [ 58 , 270 ]. This suggests that ClpP activation, but not ClpP inhibition, is the better targeting approach in breast cancers.…”

“…While ONC201 was shown to increase Poly (ADP-ribose) polymerase 1 (PARP) cleavage and apoptosis in some cancer models [ 284 , 290 ], apoptosis was not observed in breast cancers [ 269 , 270 ]. Our group was the first to report that the cytotoxicity of ONC201 is due to targeting mitochondria and is independent of TRAIL-mediated apoptosis [ 269 ].…”

“…ClpP agonists induce degradation of mitochondrial proteins (e.g., TFAM, mitochondrial elongation factor Tu [TUFM], and ETC complex proteins), depletion of mtDNA copy number, downregulation of OxPhos, loss of ATP, mitochondrial structural damage, and elevation of ROS level in multiple breast cancer cell lines [ 58 , 269 , 270 , 304 ]. Moreover, ClpP agonists dysregulate metabolic pathways not affected by other mitochondrial drugs such as metformin, oligomycin, CPI-613 [ 58 ].…”