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Cellular and Molecular Biology

Targeting the actin/tropomyosin cytoskeleton in epithelial ovarian cancer reveals multiple mechanisms of synergy with anti-microtubule agents

British Journal of Cancer volume 125, pages 265–276 (2021)Cite this article

Subjects

Abstract

Background

Anti-microtubule agents are widely used to treat ovarian cancers, but the efficacy is often compromised by drug resistance. We investigated co-targeting the actin/tropomyosin cytoskeleton and microtubules to increase treatment efficacy in ovarian cancers and potentially overcome resistance.

Methods

The presence of tropomyosin-3.1 (Tpm3.1) was examined in clinical specimens from ovarian cancer patients using immunohistochemistry. Combinatorial effects of an anti-Tpm3.1 compound, ATM-3507, with vinorelbine and paclitaxel were evaluated in ovarian cancer cells via MTS and apoptosis assays. The mechanisms of action were established using live- and fixed-cell imaging and protein analysis.

Results

Tpm3.1 is overexpressed in 97% of tumour tissues (558 of 577) representing all histotypes of epithelial ovarian cancer. ATM-3507 displayed synergy with both anti-microtubule agents to reduce cell viability. Only vinorelbine synergised with ATM-3507 in causing apoptosis. ATM-3507 significantly prolonged vinorelbine-induced mitotic arrest with elevated activity of the spindle assembly checkpoint and mitotic cell death; however, ATM-3507 showed minor impact on paclitaxel-induced mitotic defects. Both combinations substantially increased post-mitotic G1 arrest with cyclin D1 and E1 downregulation and an increase of p21Cip and p27Kip.

Conclusion

Combined targeting of Tpm3.1/actin and microtubules is a promising treatment strategy for ovarian cancer that should be further tested in clinical settings.

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Fig. 1: Representative images of Tpm3.1 IHC in patient samples with ovarian cancer and control tissues.
Fig. 2: ATM-3507 (ATM) is efficient and synergises with anti-microtubule agents, vinorelbine (VNB) and paclitaxel (PTX), in reducing the viability of ovarian cancer cells.
Fig. 3: ATM-3507 (ATM) synergistically induces apoptosis with vinorelbine (VNB) but not with paclitaxel (PTX).
Fig. 4: ATM-3507 (ATM) potentiates vinorelbine (VNB)-induced mitotic arrest with elevated activity of the spindle assembly checkpoint (SAC), resulting in an efficient mitotic cell death.
Fig. 5: ATM-3507 (ATM) and both anti-microtubule agents, vinorelbine (VNB) and paclitaxel (PTX), enhance G1/S arrest with upregulation of p21 and p27.

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Acknowledgements

We thank the Health Science Alliance Biobank from the Translational Cancer Research Network (UNSW Sydney, South Eastern Sydney Local Health District, NSW Health Pathology, Sydney, Australia) for access to tumour tissues that were used in a preliminary study to identify the extent of expression of Tpm3.1 in ovarian cancer. We thank Mr. Christopher Brownlee and Dr. Emma J. Beves (The Flow Cytometry Facility, UNSW Sydney, Sydney, Australia) for flow cytometer training and support; Dr. Michael Cornell, Dr. Elvis Pandzic, Dr. Alex Macmillan, Mrs. Iveta Slapetova and Ms. Florence C. J. Tomasetig (Biomedical Imaging Facility, UNSW Sydney, Sydney, Australia) for microscope training and support; and Dr. Michael Cornell (Biomedical Imaging Facility, UNSW Sydney, Sydney, Australia) for consulting on image data analysis.

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Authors and Affiliations

  1. School of Medical Sciences, Faculty of Medicine, University of NSW Sydney, Sydney, NSW, Australia

    Xing Xu, Yao Wang, Nicole S. Bryce, Edna C. Hardeman & Peter W. Gunning

  2. Department of Anatomical Pathology, Prince of Wales Hospital, Sydney, NSW, Australia

    Katrina Tang

  3. School of Women’s and Children’s Health, Faculty of Medicine, University of NSW Sydney, Sydney, NSW, Australia

    Nicola S. Meagher, Susan J. Ramus & Caroline E. Ford

  4. Adult Cancer Program, Lowy Cancer Research Centre, University of NSW Sydney, Sydney, NSW, Australia

    Nicola S. Meagher, Susan J. Ramus, Caroline E. Ford, Edna C. Hardeman & Peter W. Gunning

  5. Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada

    Eun Young Kang & Martin Köbel

  6. South Carolina Department of Health and Environmental Control, North Charleston, SC, USA

    Linda E. Kelemen

  7. Prince of Wales Clinical School UNSW and Department of Medical Oncology, The Prince of Wales Hospital, Sydney, NSW, Australia

    Michael Friedlander

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Contributions

X.X. designed and performed experiments, analysed the data and drafted the manuscript. Y.W. supervised the project, designed and performed experiments and drafted the manuscript. N.S.B. supervised the project and interpreted the results. K.T. analysed the data and interpreted the results. N.S.M., E.Y.K., L.E.K., M.K. and S.J.R. designed experiments and interpreted the results. M.F. initiated the research concept, designed the experimental strategy and drafted the manuscript. C.E.F. initiated the research concept and designed the experimental strategy. E.C.H. and P.W.G. initiated the research concept, designed the experimental strategy and supervised the project. All authors revised the manuscript and approved the submission of this work.

Corresponding author

Correspondence to Peter W. Gunning.

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Ethics approval and consent to participate

The study was performed with approval from the UNSW Human Research Ethics Committee (Approval # HC15771 and # HC16299). AOVT and CAL study protocols were approved by Alberta Health Services, Research Ethics and the University of Calgary, Faculty of Medicine, Office of Medical Bioethics, respectively. These study protocols used retrospective data collection from pathology reports and medical charts and were exempt by the ethics boards from requiring informed patient consent. We also declare that the study was performed in accordance with the Declaration of Helsinki.

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Not applicable.

Data availability

Digital data are kept on the server of School of Medical Sciences, UNSW Sydney and available from the corresponding author upon request.

Competing interests

P.W.G. and E.C.H. receive funding from TroBio Therapeutics, a company commercialising anti-tropomyosin drugs. P.W.G. and E.C.H. are directors and shareholders of TroBio. Other authors declare no competing interests.

Funding information

This work was supported by an Australian Department of Industry, Innovation and Science Cooperative Research Centre Project (CRC-P) grant to P.W.G. and E.C.H. and grants from the Australian Research Council (ARC grant DP160101623), the Australian National Health and Medical Research Council (NHMRC grant APP1100202, APP1079866) and The Kid’s Cancer Project to P.W.G. and E.C.H.; N.S.M. is supported by the NSW Ministry of Health and UNSW Sydney under the NSW Health PhD Scholarship Program and the Translational Cancer Research Network, a translational cancer research centre program funded by the Cancer Institute NSW (RG171797 and 15/TRC/1-03).

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Xu, X., Wang, Y., Bryce, N.S. et al. Targeting the actin/tropomyosin cytoskeleton in epithelial ovarian cancer reveals multiple mechanisms of synergy with anti-microtubule agents. Br J Cancer 125, 265–276 (2021). https://doi.org/10.1038/s41416-021-01420-y

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