TY - JOUR
T1 - Altered membrane rigidity via enhanced endogenous cholesterol synthesis drives cancer cell resistance to destruxins
AU - Heilos, Daniela
AU - Röhrl, Clemens
AU - Pirker, Christine
AU - Englinger, Bernhard
AU - Baier, Dina
AU - Mohr, Thomas
AU - Schwaiger, Michaela
AU - Iqbal, Shahid Muhammad
AU - van Schoonhoven, Sushilla
AU - Klavins, Kristaps
AU - Eberhart, Tanja
AU - Windberger, Ursula
AU - Taibon, Judith
AU - Sturm, Sonja
AU - Stuppner, Hermann
AU - Koellensperger, Gunda
AU - Dornetshuber-Fleiss, Rita
AU - Jäger, Walter
AU - Lemmens-Gruber, Rosa
AU - Berger, Walter
N1 - Funding Information:
We are grateful for the technical assistance of Mirjana Stojanovic and for the FACS analyses performed by Irene Herbacek. This work was funded by the Johanna Mahlke, geb.-Obermann-Stiftung (to Rita-Dornetshuber-Fleiss), the Fellinger Cancer Research Prize (to Walter Berger) and the Austrian Science Fund (FWF) (project number T 451-B18 to Rita-Dornetshuber-Fleiss; P25763-B13 to Clemens Röhrl). The authors gratefully acknowledge the production and characterization of destruxin congeners within the EC FP-7 INBIOSOIL project (FP7_ENV.2011.3.1.9-1 ECO-INNOVATION, INBIOSOIL, Grant Agreement No. 282767; project partner Dr. Hermann Strasser, Institute of Microbiology, University of Innsbruck, Austria).
Publisher Copyright:
© Heilos et al.
PY - 2018/5/22
Y1 - 2018/5/22
N2 - 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.
AB - 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.
KW - Cancer cell resistance
KW - Cell membrane alterations
KW - Cholesterol synthesis pathway
KW - Destruxins
KW - Mycotoxins
UR - http://www.scopus.com/inward/record.url?scp=85047432469&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.25432
DO - 10.18632/oncotarget.25432
M3 - Article
AN - SCOPUS:85047432469
SN - 1949-2553
VL - 9
SP - 25661
EP - 25680
JO - Oncotarget
JF - Oncotarget
IS - 39
ER -
