Pharmacologically targeting molecular motor promotes mitochondrial fission for anti-cancer

Abstract

Mitochondrial shape rapidly changes by dynamic balance of fusion and fission to adjust to constantly changing energy demands of cancer cells. Mitochondrial dynamics balance is exactly regulated by molecular motor consisted of myosin and actin cytoskeleton proteins. Thus, targeting myosin–actin molecular motor is considered as a promising strategy for anti-cancer. In this study, we performed a proof-of-concept study with a natural-derived small-molecule J13 to test the feasibility of anti-cancer therapeutics via pharmacologically targeting molecular motor. Here, we found J13 could directly target myosin-9 (MYH9)–actin molecular motor to promote mitochondrial fission progression, and markedly inhibited cancer cells survival, proliferation and migration. Mechanism study revealed that J13 impaired MYH9–actin interaction to inactivate molecular motor, and caused a cytoskeleton-dependent mitochondrial dynamics imbalance. Moreover, stable isotope labeling with amino acids in cell culture (SILAC) technology-coupled with pulldown analysis identified HSPA9 as a crucial adaptor protein connecting MYH9–actin molecular motor to mitochondrial fission. Taken together, we reported the first natural small-molecule directly targeting MYH9–actin molecular motor for anti-cancer translational research. Besides, our study also proved the conceptual practicability of pharmacologically disrupting mitochondrial fission/fusion dynamics in human cancer therapy.

Nascent RHOH acts as a molecular brake on actomyosin-mediated effector functions of inflammatory neutrophils

“…Molecular docking analysis suggests that RHOH spatially interacted with NMHC IIA by forming hydrogen bonds with several amino acid residues ( Fig 5B ). Among which, alanine (Ala) 655 and Ala 659 were present at the actin-binding motifs (residues 654–676) of NMHC IIA [ 50 ]. RHOH residue lysine (Lys) 34 (K34), which belongs to the switch I domain [ 51 ], was located at the interface with NMHC IIA ( Fig 5B ).…”

HBXIP blocks myosin-IIA assembly by phosphorylating and interacting with NMHC-IIA in breast cancer metastasis

“…Activation of the NMHC-IIA/TRAF6/GSK3 β axis increased the expression of its downstream gene β -catenin expression and its nuclear localization inducing EMT 13 , 54 . Natural-derived small-molecule J13 restrained the interaction between NMHC-IIA and actin molecular motor via prompting heat-shock protein A9 (HSPA9) attached to NMHC-IIA, resulting in excessive mitochondrial fission 4 . NMHC-IIA directly targeted by ruscogenin, an effective steroidal sapogenin of Radix Ophiopogon Japonicus, and mediated Toll-like receptor 4 (TLR4) interactions contributing to the development of acute lung injury 55 .…”

“…Myosin-IIA is an omnipresent molecular motor protein that binds and contracts actin filaments. In addition to its manifold cellular functions, myosin-IIA has contractile properties as a key switch of invasive and metastatic behavior 3 , 4 . Two myosin heavy chains (NMHC-IIA), encoded by MYH9 , compose the main structure of a hexameric myosin-IIA.…”

Metabolome and transcriptome analyses identify the characteristics and expression of related saponins of the three genealogical plants of bead ginseng

“…lead to a number of complications ( Sahebnasagh, Mojtahedzadeh & Najmeddin, 2020 ). Honeysuckle phenolic acids have been found to have anti-inflammatory effects and can inhibit the expression of various inflammatory factors ( Ya-ling, Hong-mei & Fu-yong, 2015 ; Jiuling, Xiaoling & Chengwen, 2013 ; Gao, Wang & Yu, 2019 ; Shin, Satsu & Bae, 2017 ; Liang & Kitts, 2018 ; Jin-qian, Zhao-ping & Heng, 2016 ; Olmos, Giner & Recio, 2007 ; Jue, Naili & Xin-sheng, 2006 ; Olmos, Giner & Recio, 2008 ; Chen, Hwang & Yu, 2016 ; Zhicong, An & Ping, 2016 ), thereby preventing SARS CoV-2 from entering the human body ( Yu, Wang & Bao, 2020 ).…”