Altered membrane rigidity via enhanced endogenous cholesterol synthesis drives cancer cell resistance to destruxins

Daniela Heilos, Clemens Röhrl, Christine Pirker, Bernhard Englinger, Dina Baier, Thomas Mohr, Michaela Schwaiger, Shahid Muhammad Iqbal, Sushilla van Schoonhoven, Kristaps Klavins, Tanja Eberhart, Ursula Windberger, Judith Taibon, Sonja Sturm, Hermann Stuppner, Gunda Koellensperger, Rita Dornetshuber-Fleiss, Walter Jäger, Rosa Lemmens-Gruber, Walter Berger

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

Abstract

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 bioinsecticides needs to be evaluated.

Original languageEnglish
Pages (from-to)25661-25680
Number of pages20
JournalOncotarget
Volume9
Issue number39
DOIs
Publication statusPublished - 22 May 2018
Externally publishedYes

Keywords

  • Cancer cell resistance
  • Cell membrane alterations
  • Cholesterol synthesis pathway
  • Destruxins
  • Mycotoxins

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