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11 results on '"Warde, Kate M"'

1. Senescence-induced immune remodeling facilitates metastatic adrenal cancer in a sex-dimorphic manner

Author

Warde, Kate M., Smith, Lorenzo J., Liu, Lihua, Stubben, Chris J., Lohman, Brian K., Willett, Parker W., Ammer, Julia L., Castaneda-Hernandez, Guadalupe, Imodoye, Sikiru O., Zhang, Chenge, Jones, Kara D., Converso-Baran, Kimber, Ekiz, H. Atakan, Barry, Marc, Clay, Michael R., Kiseljak-Vassiliades, Katja, Giordano, Thomas J., Hammer, Gary D., and Basham, Kaitlin J.

Published
2023
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4. Sublethal Hyperthermia Transiently Disrupts Cortisol Steroidogenesis in Adrenocortical Cells

Author

Mullen, Nathan, primary, Donlon, Padraig T, additional, Sebek, Jan, additional, Duffy, Katen, additional, Cappiello, Grazia, additional, Feely, Sarah, additional, Warde, Kate M, additional, Harhen, Brendan, additional, Finn, David P, additional, O'Shea, Paula M, additional, Prakash, Punit, additional, O’Halloran, Martin, additional, and Dennedy, Michael C, additional

Published
2023
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7. Mitotane Targets Lipid Droplets to Induce Lipolysis in Adrenocortical Carcinoma

Author

Warde, Kate M; https://orcid.org/0000-0001-6147-294X, Lim, Yi Jan, Ribes Martinez, Eduardo, Beuschlein, Felix; https://orcid.org/0000-0001-7826-3984, O'Shea, Paula, Hantel, Constanze, Dennedy, Michael Conall; https://orcid.org/0000-0001-9325-6520, Warde, Kate M; https://orcid.org/0000-0001-6147-294X, Lim, Yi Jan, Ribes Martinez, Eduardo, Beuschlein, Felix; https://orcid.org/0000-0001-7826-3984, O'Shea, Paula, Hantel, Constanze, and Dennedy, Michael Conall; https://orcid.org/0000-0001-9325-6520

Abstract

INTRODUCTION Adrenocortical carcinoma (ACC) is a rare aggressive cancer with low overall survival. Adjuvant mitotane improves survival but is limited by poor response rates and resistance. Mitotane's efficacy is attributed to the accumulation of toxic free cholesterol, predominantly through cholesterol storage inhibition. However, targeting this pathway has proven unsuccessful. We hypothesize that mitotane-induced free-cholesterol accumulation is also mediated through enhanced breakdown of lipid droplets. METHODOLOGY ATCC-H295R (mitotane-sensitive) and MUC-1 (mitotane-resistant) ACC cells were evaluated for lipid content using specific BODIPY dyes. Protein expression was evaluated by immunoblotting and flow cytometry. Cell viability was measured by quantifying propidium iodide-positive cells following mitotane treatment and pharmacological inhibitors of lipolysis. RESULTS H295R and MUC-1 cells demonstrated similar neutral lipid droplet numbers at baseline. However, evaluation of lipid machinery demonstrated distinct profiles in each model. Analysis of intracellular lipid droplet content showed H295R cells preferentially store cholesteryl esters, whereas MUC-1 cells store triacylglycerol. Decreased lipid droplets were associated with increased lipolysis in H295R and in MUC-1 at toxic mitotane concentrations. Pharmacological inhibition of lipolysis attenuated mitotane-induced toxicity in both models. CONCLUSION We highlight that lipid droplet breakdown and activation of lipolysis represent a putative additional mechanism for mitotane-induced cytotoxicity in ACC. Further understanding of cholesterol and lipids in ACC offers potential novel therapeutic exploitation, especially in mitotane-resistant disease.

Published
2022

10. Liver X receptor inhibition potentiates mitotane induced adrenotoxicity in ACC

Author

Warde, Kate M, Schoenmakers, Erik, Ribes Martínez, Eduardo, Lim, Yi-Jan, Leonard, Maeve, Lawless, Sarah J, O'Shea, Paula, Chatterjee, V Krishna, Gurnell, Mark, Hantel, Constanze, Dennedy, Michael Conall, Schoenmakers, Erik [0000-0003-0674-8282], Chatterjee, Krishna [0000-0002-2654-8854], Gurnell, Mark [0000-0001-5745-6832], and Apollo - University of Cambridge Repository

Subjects
mitotane, adrenal, liver X receptor alpha, Adrenocortical Carcinoma, cholesterol, Humans, lipids (amino acids, peptides, and proteins), Apoptosis, Female, Middle Aged, Transfection, Liver X Receptors
Abstract

Adrenocortical carcinoma (ACC) is a rare aggressive malignancy with a poor outcome largely due to limited treatment options. Here, we propose a novel therapeutic approach through modulating intracellular free cholesterol via the liver X receptor alpha (LXRα) in combination with current first line pharmacotherapy, mitotane. H295R and MUC-1 ACC cell lines were pretreated with LXRα inhibitors in combination with mitotane. In H295R, mitotane (20, 40, 50µM) induced dose-dependent cell death, however, in MUC-1 this only occurred at a supratherapeutic concentration (200µM). LXRα inhibition potentiated mitotane-induced cytotoxicity in both cell lines. This was confirmed through use of the CompuSyn model which showed moderate pharmacological synergism and was indicative of apoptotic cell death via an increase in annexinV and cleaved-caspase 3 expression. Inhibition of LXRα was confirmed through downregulation of cholesterol efflux pumps ABCA1 and ABCG1, however, combination treatment with mitotane attenuated this effect. Intracellular free cholesterol levels were associated with increased cytotoxicity in H295R (r2=0.5210) and MUC-1 (r2=0.9299) cells. While both cell lines exhibited similar levels of free cholesterol at baseline, H295R were cholesterol ester rich whereas MUC-1 were cholesterol ester poor. We highlight the importance of LXRα mediated cholesterol metabolism in the management of ACC, drawing attention to its role in the therapeutics of mitotane sensitive tumours. We also demonstrate significant differences in cholesterol storage between mitotane sensitive and resistant disease.

Published
2020
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