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Multi-nucleated cells use ROS to induce breast cancer chemo-resistance in vitro and in vivo

Oncogene volume 37, pages 4546–4561 (2018)Cite this article

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Abstract

Although there is a strong correlation between multinucleated cells (MNCs) and cancer chemo-resistance in variety of cancers, our understanding of how multinucleated cells modulate the tumor micro-environment is limited. We captured multinucleated cells from triple-negative chemo-resistant breast cancers cells in a time frame, where they do not proliferate but rather significantly regulate their micro-environment. We show that oxidatively stressed MNCs induce chemo-resistance in vitro and in vivo by secreting VEGF and MIF. These factors act through the RAS/MAPK pathway to induce chemo-resistance by upregulating anti-apoptotic proteins. In MNCs, elevated reactive oxygen species (ROS) stabilizes HIF-1α contributing to increase production of VEGF and MIF. Together the data indicate, that the ROS-HIF-1α signaling axis is very crucial in regulation of chemo-resistance by MNCs. Targeting ROS-HIF-1α in future may help to abrogate drug resistance in breast cancer.

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Acknowledgements

We acknowledge Anji Anura, Bodhisatwa Das, Raunak Kumar Das, and Prof. Jyotirmoy Chaterjee from IIT Kharagpur for their help in microscopy. We also thank Hasini Jayatilaka and Michelle Karl from Johns Hopkins University for their support. We also thank Sanat Dey, Purna Patra, and other staffs of central research facility of IIT Kharagpur for technical assistance. The research was supported by Department of Biotechnology (BT/PR13996/Med/30/309/2010), Department of Atomic Energy, (35/14/05/2015-BRNS/3053), and Ministry of Human Resource Development (F. NO. 4-23/2014-TS.I). University Grants Commission, Department of Biotechnology, and Fulbright is also hereby acknowledged for scholarship support.

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Authors and Affiliations

  1. School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, 721302, India

    Aditya Parekh, Subhayan Das, Sheetal Parida, Chandan Kanta Das, B. N. Prashanth Kumar, Rashmi Bharti, Goutam Dey, Kacoli Banerjee, Shashi Rajput, Deblina Bharadwaj, Ipsita Pal, Kaushik kumar Dey, Yetirajam Rajesh, Bikash Chandra Jena, Angana Biswas, Payel Banik, Santanu Dhara & Mahitosh Mandal

  2. Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, 721302, India

    Debabrata Dutta & Amit Kumar Das

  3. BD Biosciences-Centre for Research in Nanoscience and Nanotechnology, University of Calcutta, Kolkata, West Bengal, India

    Sanjaya K. Mallick

  4. Department of chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA

    Pei-Hsun Wu & Denis Wirtz

  5. Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, 23298, USA

    Anjan K. Pradhan, Swadesh K. Das & Paul B. Fisher

  6. Department of Systems Biology, Division of Cancer Medicine, MD Anderson Cancer Center, Houston, TX, 77030, USA

    Gordon B. Mills

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Parekh, A., Das, S., Parida, S. et al. Multi-nucleated cells use ROS to induce breast cancer chemo-resistance in vitro and in vivo. Oncogene 37, 4546–4561 (2018). https://doi.org/10.1038/s41388-018-0272-6

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