Miclxin, a Novel MIC60 Inhibitor, Induces Apoptosis via Mitochondrial Stress in β-Catenin Mutant Tumor Cells

Abstract

The Wnt signaling pathway regulates diverse cellular processes. β-Catenin is one of the major components of this pathway, in which it plays a main role. Although it has been established that β-catenin is mutated in a wide variety of tumors, there are currently no effective therapeutic agents that target β-catenin. In this study, we searched for the compound that targets mutant β-catenin and found DS37262926 (miclxin). Miclxin exhibited β-catenin-dependent apoptosis in βcatenin-mutated HCT116 cells and isogenic HCT116 (CTNNB1 Δ45/ −) cells; however, this effect was not observed in isogenic HCT116 (CTNNB1 +/−) cells. Using miclxin-immobilized beads, MIC60, one of the major components of the mitochondrial contact site and cristae organizing system (MICOS) complex, was identified as a target protein of miclxin. We revealed that MIC60 dysfunction caused by miclxin induced a mitochondrial stress response in a mutant β-catenin-dependent manner. Activation of the mitochondrial stress response was responsible for the downregulation of Bcl-2, leading to severe loss of mitochondrial membrane potential and subsequent apoptosisinducing factor-dependent apoptosis. Our findings suggest that targeting MIC60 is a potential strategy with which tumor cells can be killed through induction of severe mitochondrial damage in a mutant β-catenin-dependent manner.

Morphological changes of mitochondria-related to apoptosis during postmortem aging of beef muscles

“…A vital component of the MICOS complex, Mic60 was essential for maintaining the shape of the mitochondrial cristae ( Harner et al, 2011 ). Mic60 interacted with several protein complexes in the outer mitochondrial membrane, which are strongly associated with mitochondrial apoptosis, in addition to taking a role in the regulation of cristae and cristae junction formation ( Ikeda et al, 2020 ). In the current study, Mic60 expression increased at 0–6 h PM and then dramatically declined at 24–120 h ( Fig.…”

The Emerging Roles of Silver Nanoparticles to Target Viral Life Cycle and Detect Viral Pathogens

“…Apoptosis is a programmed cell death that could either be a host-defensive mechanism to protect the spread of invasive pathogens or a pathogen induced phenomenon to inflict large scale damage to bodily tissues. [66,67] Originally, it was hypothesized that apoptosis does not provoke the inflammatory system of the body, [68] only to be disputed and reinstated later that it could indeed activate the immune response. [69] Immunomodulation is an artful strategy employed by viruses to escape detection by host immune responses as well as obstruct signaling mechanisms that antagonize their survival and even deploy favorable mechanisms that promote their survival.…”

“…Additionally, there are other intracellular factors that govern the fate of virus replication inside cells like apoptosis and autophagy. Apoptosis is a programmed cell death that could either be a host‐defensive mechanism to protect the spread of invasive pathogens or a pathogen induced phenomenon to inflict large scale damage to bodily tissues [66,67] . Originally, it was hypothesized that apoptosis does not provoke the inflammatory system of the body, [68] only to be disputed and reinstated later that it could indeed activate the immune response [69]…”