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Soft drug-resistant ovarian cancer cells migrate via two distinct mechanisms utilizing myosin II-based contractility.

Authors
  • Kapoor, Aastha1
  • Barai, Amlan1
  • Thakur, Bhushan2
  • Das, Alakesh1
  • Patwardhan, Sejal R1
  • Monteiro, Melissa1
  • Gaikwad, Snehal2
  • Bukhari, Amirali B2
  • Mogha, Pankaj3
  • Majumder, Abhijit3
  • De, Abhijit2
  • Ray, Pritha4
  • Sen, Shamik5
  • 1 Department of Biosciences and Bioengineering, IIT Bombay, India. , (India)
  • 2 Tata Memorial Centre, ACTREC, Navi Mumbai, and Homi Bhabha National Institute, Anushakti Nagar, Mumbai, India. , (India)
  • 3 Department of Chemical Engineering, IIT Bombay, India. , (India)
  • 4 Tata Memorial Centre, ACTREC, Navi Mumbai, and Homi Bhabha National Institute, Anushakti Nagar, Mumbai, India. Electronic address: [email protected] , (India)
  • 5 Department of Biosciences and Bioengineering, IIT Bombay, India. Electronic address: [email protected] , (India)
Type
Published Article
Journal
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
Publisher
Elsevier
Publication Date
Feb 01, 2018
Volume
1865
Issue
2
Pages
392–405
Identifiers
DOI: 10.1016/j.bbamcr.2017.11.012
PMID: 29175377
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

The failure of chemotherapeutic drugs in treatment of various cancers is attributed to the acquisition of drug resistance. However, the migration mechanisms of drug-resistant cancer cells remain incompletely understood. Here we address this question from a biophysical perspective by mapping the phenotypic alterations in ovarian cancer cells (OCCs) resistant to cisplatin and paclitaxel. We show that cisplatin-resistant (CisR), paclitaxel-resistant (PacR) and dual drug-resistant (i.e., resistant to both drugs) OCCs are more contractile and softer than drug-sensitive cells. Protease inhibition suppresses invasion of CisR cells but not of PacR cells, indicative of a protease-dependent mode of migration in CisR cells and a protease-independent mode of migration in PacR. Despite these differences, actomyosin contractility, mediated by the RhoA-ROCK2-Myosin II signaling pathway, regulates both modes of migration. Confined migration experiments establish the role of myosin IIA and IIB in mediating nuclear translocation and regulation of proteolytic activity. Collectively, our results highlight the importance of myosin II as a potential therapeutic target for treatment of drug-resistant ovarian cancer cells. Copyright © 2017 Elsevier B.V. All rights reserved.

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