PMID- 37875071
OWN - NLM
STAT- MEDLINE
DCOM- 20231026
LR  - 20231027
IS  - 1879-0445 (Electronic)
IS  - 0960-9822 (Linking)
VI  - 33
IP  - 20
DP  - 2023 Oct 23
TI  - Cortical tension drug screen links mitotic spindle integrity to Rho pathway.
PG  - 4458-4469.e4
LID - S0960-9822(23)01268-X [pii]
LID - 10.1016/j.cub.2023.09.022 [doi]
AB  - Mechanical force generation plays an essential role in many cellular functions, 
      including mitosis. Actomyosin contractile forces mediate changes in cell shape in 
      mitosis and are implicated in mitotic spindle integrity via cortical tension. An 
      unbiased screen of 150 small molecules that impact actin organization and 32 
      anti-mitotic drugs identified two molecular targets, Rho kinase (ROCK) and 
      tropomyosin 3.1/2 (Tpm3.1/2), whose inhibition has the greatest impact on mitotic 
      cortical tension. The converse was found for compounds that depolymerize 
      microtubules. Tpm3.1/2 forms a co-polymer with mitotic cortical actin filaments, 
      and its inhibition prevents rescue of multipolar spindles induced by 
      anti-microtubule chemotherapeutics. We examined the role of mitotic cortical 
      tension in this rescue mechanism. Inhibition of ROCK and Tpm3.1/2 and knockdown 
      (KD) of cortical nonmuscle myosin 2A (NM2A), all of which reduce cortical 
      tension, inhibited rescue of multipolar mitotic spindles, further implicating 
      cortical tension in the rescue mechanism. GEF-H1 released from microtubules by 
      depolymerization increased cortical tension through the RhoA pathway, and its KD 
      also inhibited rescue of multipolar mitotic spindles. We conclude that 
      microtubule depolymerization by anti-cancer drugs induces cortical-tension-based 
      rescue to ensure integrity of the mitotic bipolar spindle mediated via the RhoA 
      pathway. Central to this mechanism is the dependence of NM2A on Tpm3.1/2 to 
      produce the functional engagement of actin filaments responsible for cortical 
      tension.
CI  - Copyright (c) 2023 Elsevier Inc. All rights reserved.
FAU - Wang, Dejiang
AU  - Wang D
AD  - Institute for Biomedical Materials and Devices (IBMD), Faculty of Science, 
      University of Technology Sydney, Sydney, NSW 2007, Australia; School of 
      Biomedical Sciences, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW 
      2052, Australia.
FAU - Wang, Yao
AU  - Wang Y
AD  - School of Biomedical Sciences, Faculty of Medicine and Health, UNSW Sydney, 
      Sydney, NSW 2052, Australia.
FAU - Di, Xiangjun
AU  - Di X
AD  - Institute for Biomedical Materials and Devices (IBMD), Faculty of Science, 
      University of Technology Sydney, Sydney, NSW 2007, Australia.
FAU - Wang, Fan
AU  - Wang F
AD  - School of Electrical and Data Engineering, Faculty of Engineering and Information 
      Technology, University of Technology Sydney, Sydney, NSW 2007, Australia; School 
      of Physics, Beihang University, Beijing 100191, P.R. China.
FAU - Wanninayaka, Amanda
AU  - Wanninayaka A
AD  - School of Biomedical Sciences, Faculty of Medicine and Health, UNSW Sydney, 
      Sydney, NSW 2052, Australia.
FAU - Carnell, Michael
AU  - Carnell M
AD  - Katharina Gaus Light Microscope Facility, Mark Wainwright Analytical Centre, UNSW 
      Sydney, Sydney, NSW 2052, Australia.
FAU - Hardeman, Edna C
AU  - Hardeman EC
AD  - School of Biomedical Sciences, Faculty of Medicine and Health, UNSW Sydney, 
      Sydney, NSW 2052, Australia.
FAU - Jin, Dayong
AU  - Jin D
AD  - Institute for Biomedical Materials and Devices (IBMD), Faculty of Science, 
      University of Technology Sydney, Sydney, NSW 2007, Australia; UTS-SUStech Joint 
      Research Centre for Biomedical Materials & Devices, Department of Biomedical 
      Engineering, Southern University of Science and Technology, Shenzhen 518055, P.R. 
      China.
FAU - Gunning, Peter W
AU  - Gunning PW
AD  - School of Biomedical Sciences, Faculty of Medicine and Health, UNSW Sydney, 
      Sydney, NSW 2052, Australia. Electronic address: p.gunning@unsw.edu.au.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20231013
PL  - England
TA  - Curr Biol
JT  - Current biology : CB
JID - 9107782
RN  - 0 (Actins)
RN  - EC 3.6.4.1 (Myosins)
SB  - IM
MH  - *Spindle Apparatus/metabolism
MH  - *Microtubules/metabolism
MH  - Actins/metabolism
MH  - Mitosis
MH  - Actin Cytoskeleton/metabolism
MH  - Myosins/metabolism
OTO - NOTNLM
OT  - NM2A
OT  - ROCK
OT  - Tpm3.1
OT  - actin
OT  - astral microtubules
OT  - cell cortex
OT  - cortical tension
OT  - microtubule depolymerizers
OT  - mitotic spindle
OT  - tropomyosin
COIS- Declaration of interests P.W.G. and E.C.H. are directors and shareholders of 
      TroBio Therapeutics Pty Ltd., a company that is commercializing anti-tropomyosin 
      drugs for the treatment of cancer. Further, their labs receive funding from 
      TroBio to evaluate anti-tropomyosin drug candidates.
EDAT- 2023/10/25 00:42
MHDA- 2023/10/26 06:42
CRDT- 2023/10/24 18:16
PHST- 2022/11/09 00:00 [received]
PHST- 2023/07/24 00:00 [revised]
PHST- 2023/09/11 00:00 [accepted]
PHST- 2023/10/26 06:42 [medline]
PHST- 2023/10/25 00:42 [pubmed]
PHST- 2023/10/24 18:16 [entrez]
AID - S0960-9822(23)01268-X [pii]
AID - 10.1016/j.cub.2023.09.022 [doi]
PST - ppublish
SO  - Curr Biol. 2023 Oct 23;33(20):4458-4469.e4. doi: 10.1016/j.cub.2023.09.022. Epub 
      2023 Oct 13.