【摘 要】
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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 regu-lated by molecular motor consisted of myosin and actin cytoskeleton
【机 构】
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State Key Laboratory of Natural and Biomimetic Drugs,School of Pharmaceutical Sciences,Peking Univer
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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 regu-lated 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 mitochon-drial 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 mitochon-drial fission/fusion dynamics in human cancer therapy.
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