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Misfolded Proteins: From Little Villains to Little Helpers in the Fight Against Cancer

The application of cytostatic drugs targeting the high proliferation rates of cancer cells is currently the most commonly used treatment option in cancer chemotherapy. However, severe side effects and resistance mechanisms may occur as a result of such treatment, possibly limiting the therapeutic ef...

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Detalles Bibliográficos
Autores principales: Brüning, Ansgar, Jückstock, Julia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338749/
https://www.ncbi.nlm.nih.gov/pubmed/25759792
http://dx.doi.org/10.3389/fonc.2015.00047
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author Brüning, Ansgar
Jückstock, Julia
author_facet Brüning, Ansgar
Jückstock, Julia
author_sort Brüning, Ansgar
collection PubMed
description The application of cytostatic drugs targeting the high proliferation rates of cancer cells is currently the most commonly used treatment option in cancer chemotherapy. However, severe side effects and resistance mechanisms may occur as a result of such treatment, possibly limiting the therapeutic efficacy of these agents. In recent years, several therapeutic strategies have been developed that aim at targeting not the genomic integrity and replication machinery of cancer cells but instead their protein homeostasis. During malignant transformation, the cancer cell proteome develops vast aberrations in the expression of mutated proteins, oncoproteins, drug- and apoptosis-resistance proteins, etc. A complex network of protein quality-control mechanisms, including chaperoning by heat shock proteins (HSPs), not only is essential for maintaining the extravagant proteomic lifestyle of cancer cells but also represents an ideal cancer-specific target to be tackled. Furthermore, the high rate of protein synthesis and turnover in certain types of cancer cells can be specifically directed by interfering with the proteasomal and autophagosomal protein recycling and degradation machinery, as evidenced by the clinical application of proteasome inhibitors. Since proteins with loss of their native conformation are prone to unspecific aggregations and have proved to be detrimental to normal cellular function, specific induction of misfolded proteins by HSP inhibitors, proteasome inhibitors, hyperthermia, or inducers of endoplasmic reticulum stress represents a new method of cancer cell killing exploitable for therapeutic purposes. This review describes drugs – approved, repurposed, or under investigation – that can be used to accumulate misfolded proteins in cancer cells, and particularly focuses on the molecular aspects that lead to the cytotoxicity of misfolded proteins in cancer cells.
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spelling pubmed-43387492015-03-10 Misfolded Proteins: From Little Villains to Little Helpers in the Fight Against Cancer Brüning, Ansgar Jückstock, Julia Front Oncol Oncology The application of cytostatic drugs targeting the high proliferation rates of cancer cells is currently the most commonly used treatment option in cancer chemotherapy. However, severe side effects and resistance mechanisms may occur as a result of such treatment, possibly limiting the therapeutic efficacy of these agents. In recent years, several therapeutic strategies have been developed that aim at targeting not the genomic integrity and replication machinery of cancer cells but instead their protein homeostasis. During malignant transformation, the cancer cell proteome develops vast aberrations in the expression of mutated proteins, oncoproteins, drug- and apoptosis-resistance proteins, etc. A complex network of protein quality-control mechanisms, including chaperoning by heat shock proteins (HSPs), not only is essential for maintaining the extravagant proteomic lifestyle of cancer cells but also represents an ideal cancer-specific target to be tackled. Furthermore, the high rate of protein synthesis and turnover in certain types of cancer cells can be specifically directed by interfering with the proteasomal and autophagosomal protein recycling and degradation machinery, as evidenced by the clinical application of proteasome inhibitors. Since proteins with loss of their native conformation are prone to unspecific aggregations and have proved to be detrimental to normal cellular function, specific induction of misfolded proteins by HSP inhibitors, proteasome inhibitors, hyperthermia, or inducers of endoplasmic reticulum stress represents a new method of cancer cell killing exploitable for therapeutic purposes. This review describes drugs – approved, repurposed, or under investigation – that can be used to accumulate misfolded proteins in cancer cells, and particularly focuses on the molecular aspects that lead to the cytotoxicity of misfolded proteins in cancer cells. Frontiers Media S.A. 2015-02-24 /pmc/articles/PMC4338749/ /pubmed/25759792 http://dx.doi.org/10.3389/fonc.2015.00047 Text en Copyright © 2015 Brüning and Jückstock. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Brüning, Ansgar
Jückstock, Julia
Misfolded Proteins: From Little Villains to Little Helpers in the Fight Against Cancer
title Misfolded Proteins: From Little Villains to Little Helpers in the Fight Against Cancer
title_full Misfolded Proteins: From Little Villains to Little Helpers in the Fight Against Cancer
title_fullStr Misfolded Proteins: From Little Villains to Little Helpers in the Fight Against Cancer
title_full_unstemmed Misfolded Proteins: From Little Villains to Little Helpers in the Fight Against Cancer
title_short Misfolded Proteins: From Little Villains to Little Helpers in the Fight Against Cancer
title_sort misfolded proteins: from little villains to little helpers in the fight against cancer
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338749/
https://www.ncbi.nlm.nih.gov/pubmed/25759792
http://dx.doi.org/10.3389/fonc.2015.00047
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