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Altered membrane rigidity via enhanced endogenous cholesterol synthesis drives cancer cell resistance to destruxins
Destruxins, secondary metabolites of entomopathogenic fungi, exert a wide variety of interesting characteristics ranging from antiviral to anticancer effects. Although their mode of action was evaluated previously, the molecular mechanisms of resistance development are unknown. Hence, we have establ...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5986646/ https://www.ncbi.nlm.nih.gov/pubmed/29876015 http://dx.doi.org/10.18632/oncotarget.25432 |
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author | Heilos, Daniela Röhrl, Clemens Pirker, Christine Englinger, Bernhard Baier, Dina Mohr, Thomas Schwaiger, Michaela Iqbal, Shahid Muhammad van Schoonhoven, Sushilla Klavins, Kristaps Eberhart, Tanja Windberger, Ursula Taibon, Judith Sturm, Sonja Stuppner, Hermann Koellensperger, Gunda Dornetshuber-Fleiss, Rita Jäger, Walter Lemmens-Gruber, Rosa Berger, Walter |
author_facet | Heilos, Daniela Röhrl, Clemens Pirker, Christine Englinger, Bernhard Baier, Dina Mohr, Thomas Schwaiger, Michaela Iqbal, Shahid Muhammad van Schoonhoven, Sushilla Klavins, Kristaps Eberhart, Tanja Windberger, Ursula Taibon, Judith Sturm, Sonja Stuppner, Hermann Koellensperger, Gunda Dornetshuber-Fleiss, Rita Jäger, Walter Lemmens-Gruber, Rosa Berger, Walter |
author_sort | Heilos, Daniela |
collection | PubMed |
description | Destruxins, secondary metabolites of entomopathogenic fungi, exert a wide variety of interesting characteristics ranging from antiviral to anticancer effects. Although their mode of action was evaluated previously, the molecular mechanisms of resistance development are unknown. Hence, we have established destruxin-resistant sublines of HCT116 colon carcinoma cells by selection with the most prevalent derivatives, destruxin (dtx)A, dtxB and dtxE. Various cell biological and molecular techniques were applied to elucidate the regulatory mechanisms underlying these acquired and highly stable destruxin resistance phenotypes. Interestingly, well-known chemoresistance-mediating ABC efflux transporters were not the major players. Instead, in dtxA- and dtxB-resistant cells a hyper-activated mevalonate pathway was uncovered resulting in increased de-novo cholesterol synthesis rates and elevated levels of lanosterol, cholesterol as well as several oxysterol metabolites. Accordingly, inhibition of the mevalonate pathway at two different steps, using either statins or zoledronic acid, significantly reduced acquired but also intrinsic destruxin resistance. Vice versa, cholesterol supplementation protected destruxin-sensitive cells against their cytotoxic activity. Additionally, an increased cell membrane adhesiveness of dtxA-resistant as compared to parental cells was detected by atomic force microscopy. This was paralleled by a dramatically reduced ionophoric capacity of dtxA in resistant cells when cultured in absence but not in presence of statins. Summarizing, our results suggest a reduced ionophoric activity of destruxins due to cholesterol-mediated plasma membrane re-organization as molecular mechanism underlying acquired destruxin resistance in human colon cancer cells. Whether this mechanism might be valid also in other cell types and organisms exposed to destruxins e.g. as bio-insecticides needs to be evaluated. |
format | Online Article Text |
id | pubmed-5986646 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-59866462018-06-06 Altered membrane rigidity via enhanced endogenous cholesterol synthesis drives cancer cell resistance to destruxins Heilos, Daniela Röhrl, Clemens Pirker, Christine Englinger, Bernhard Baier, Dina Mohr, Thomas Schwaiger, Michaela Iqbal, Shahid Muhammad van Schoonhoven, Sushilla Klavins, Kristaps Eberhart, Tanja Windberger, Ursula Taibon, Judith Sturm, Sonja Stuppner, Hermann Koellensperger, Gunda Dornetshuber-Fleiss, Rita Jäger, Walter Lemmens-Gruber, Rosa Berger, Walter Oncotarget Research Paper Destruxins, secondary metabolites of entomopathogenic fungi, exert a wide variety of interesting characteristics ranging from antiviral to anticancer effects. Although their mode of action was evaluated previously, the molecular mechanisms of resistance development are unknown. Hence, we have established destruxin-resistant sublines of HCT116 colon carcinoma cells by selection with the most prevalent derivatives, destruxin (dtx)A, dtxB and dtxE. Various cell biological and molecular techniques were applied to elucidate the regulatory mechanisms underlying these acquired and highly stable destruxin resistance phenotypes. Interestingly, well-known chemoresistance-mediating ABC efflux transporters were not the major players. Instead, in dtxA- and dtxB-resistant cells a hyper-activated mevalonate pathway was uncovered resulting in increased de-novo cholesterol synthesis rates and elevated levels of lanosterol, cholesterol as well as several oxysterol metabolites. Accordingly, inhibition of the mevalonate pathway at two different steps, using either statins or zoledronic acid, significantly reduced acquired but also intrinsic destruxin resistance. Vice versa, cholesterol supplementation protected destruxin-sensitive cells against their cytotoxic activity. Additionally, an increased cell membrane adhesiveness of dtxA-resistant as compared to parental cells was detected by atomic force microscopy. This was paralleled by a dramatically reduced ionophoric capacity of dtxA in resistant cells when cultured in absence but not in presence of statins. Summarizing, our results suggest a reduced ionophoric activity of destruxins due to cholesterol-mediated plasma membrane re-organization as molecular mechanism underlying acquired destruxin resistance in human colon cancer cells. Whether this mechanism might be valid also in other cell types and organisms exposed to destruxins e.g. as bio-insecticides needs to be evaluated. Impact Journals LLC 2018-05-22 /pmc/articles/PMC5986646/ /pubmed/29876015 http://dx.doi.org/10.18632/oncotarget.25432 Text en Copyright: © 2018 Heilos et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Heilos, Daniela Röhrl, Clemens Pirker, Christine Englinger, Bernhard Baier, Dina Mohr, Thomas Schwaiger, Michaela Iqbal, Shahid Muhammad van Schoonhoven, Sushilla Klavins, Kristaps Eberhart, Tanja Windberger, Ursula Taibon, Judith Sturm, Sonja Stuppner, Hermann Koellensperger, Gunda Dornetshuber-Fleiss, Rita Jäger, Walter Lemmens-Gruber, Rosa Berger, Walter Altered membrane rigidity via enhanced endogenous cholesterol synthesis drives cancer cell resistance to destruxins |
title | Altered membrane rigidity via enhanced endogenous cholesterol synthesis drives cancer cell resistance to destruxins |
title_full | Altered membrane rigidity via enhanced endogenous cholesterol synthesis drives cancer cell resistance to destruxins |
title_fullStr | Altered membrane rigidity via enhanced endogenous cholesterol synthesis drives cancer cell resistance to destruxins |
title_full_unstemmed | Altered membrane rigidity via enhanced endogenous cholesterol synthesis drives cancer cell resistance to destruxins |
title_short | Altered membrane rigidity via enhanced endogenous cholesterol synthesis drives cancer cell resistance to destruxins |
title_sort | altered membrane rigidity via enhanced endogenous cholesterol synthesis drives cancer cell resistance to destruxins |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5986646/ https://www.ncbi.nlm.nih.gov/pubmed/29876015 http://dx.doi.org/10.18632/oncotarget.25432 |
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