Ho Zhi Guang, Matthew and Kavanagh, Emma L. and Dunne, Luke Paul and Dowling, Paul and Zhang, Li and Lindsay, Sinéad and Bazou, Despina and Goh, Chia Yin and Hanley, Cathal and Bianchi, Giada and Anderson, Kenneth C. and O'Gorman, Peter and McCann, Amanda (2019) Targeting Proteotoxic Stress in Cancer: A Review of the Role that Protein Quality Control Pathways Play in Oncogenesis. Cancers, 11 (66). ISSN 2072-6694

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Abstract

Despite significant advances in cancer diagnostics and therapeutics the majority of cancer unfortunately remains incurable, which has led to continued research to better understand its exceptionally diverse biology. As a result of genomic instability, cancer cells typically have elevated proteotoxic stress. Recent appreciation of this functional link between the two secondary hallmarks of cancer: aneuploidy (oxidative stress) and proteotoxic stress, has therefore led to the development of new anticancer therapies targeting this emerging “Achilles heel” of malignancy. This review highlights the importance of managing proteotoxic stress for cancer cell survival and provides an overview of the integral role proteostasis pathways play in the maintenance of protein homeostasis. We further review the efforts undertaken to exploit proteotoxic stress in multiple myeloma (as an example of a hematologic malignancy) and triple negative breast cancer (as an example of a solid tumor), and give examples of: (1) FDA-approved therapies in routine clinical use; and (2) promising therapies currently in clinical trials. Finally, we provide new insights gleaned from the use of emerging technologies to disrupt the protein secretory pathway and repurpose E3 ligases to achieve targeted protein degradation.

Item Type:	Article
Additional Information:	© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). Cite as: Ho Zhi Guang, M.; Kavanagh, E.L.; Dunne, L.P.; Dowling, P.; Zhang, L.; Lindsay, S.; Bazou, D.; Goh, C.Y.; Hanley, C.; Bianchi, G.; Anderson, K.C.; O’Gorman, P.; McCann, A. Targeting Proteotoxic Stress in Cancer: A Review of the Role that Protein Quality Control Pathways Play in Oncogenesis. Cancers 2019, 11, 66. Funding: Funding is acknowledged from the UCD Wellcome Institutional Strategic Support Fund, which was financed jointly by University College Dublin and the SFI-HRB-Wellcome Biomedical Research Partnership (ref 204844/Z/16/Z) (A.M. and S.L). Funding is also acknowledged from The Mater Foundation, Mater Misericordiae University Hospital (MMUH) Dublin Ireland (E.L.K).
Keywords:	proteotoxic stress; chemoresistance; proteasome; unfolded protein response; autophagy; multiple myeloma; triple negative breast cancer; protein quality control;
Academic Unit:	Faculty of Science and Engineering > Biology
Item ID:	13579
Identification Number:	https://doi.org/10.3390/cancers11010066
Depositing User:	Paul Dowling
Date Deposited:	18 Nov 2020 16:33
Journal or Publication Title:	Cancers
Publisher:	MDPI
Refereed:	Yes
Funders:	UCD Wellcome Institutional Strategic Support Fund, The Mater Foundation, Mater Misericordiae University Hospital (MMUH)
URI:	Publisher
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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