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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics
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Cancer Biology and Translational Studies

Statins Reduce Intratumor Cholesterol Affecting Adrenocortical Cancer Growth

Francesca Trotta, Paola Avena, Adele Chimento, Vittoria Rago, Arianna De Luca, Sara Sculco, Marta C. Nocito, Rocco Malivindi, Francesco Fallo, Raffaele Pezzani, Catia Pilon, Francesco M. Lasorsa, Simona N. Barile, Luigi Palmieri, Antonio M. Lerario, Vincenzo Pezzi, Ivan Casaburi and Rosa Sirianni
Francesca Trotta
1Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy.
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Paola Avena
1Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy.
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Adele Chimento
1Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy.
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Vittoria Rago
1Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy.
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Arianna De Luca
1Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy.
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Sara Sculco
1Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy.
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Marta C. Nocito
1Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy.
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Rocco Malivindi
1Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy.
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Francesco Fallo
2Department of Medical and Surgical Sciences, University of Padua, Padua, Italy.
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Raffaele Pezzani
2Department of Medical and Surgical Sciences, University of Padua, Padua, Italy.
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Catia Pilon
2Department of Medical and Surgical Sciences, University of Padua, Padua, Italy.
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Francesco M. Lasorsa
3Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, and CNR Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, Bari, Italy.
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Simona N. Barile
3Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, and CNR Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, Bari, Italy.
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Luigi Palmieri
3Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, and CNR Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, Bari, Italy.
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Antonio M. Lerario
4Departments of Molecular and Integrative Physiology and Internal Medicine, University of Michigan, Medical School, Ann Arbor, Michigan.
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Vincenzo Pezzi
1Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy.
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  • For correspondence: rosa.sirianni@unical.it v.pezzi@unical.it
Ivan Casaburi
1Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy.
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Rosa Sirianni
1Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy.
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  • For correspondence: rosa.sirianni@unical.it v.pezzi@unical.it
DOI: 10.1158/1535-7163.MCT-19-1063 Published September 2020
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Abstract

Mitotane causes hypercholesterolemia in patients with adrenocortical carcinoma (ACC). We suppose that cholesterol increases within the tumor and can be used to activate proliferative pathways. In this study, we used statins to decrease intratumor cholesterol and investigated the effects on ACC growth related to estrogen receptor α (ERα) action at the nuclear and mitochondrial levels. We first used microarray to investigate mitotane effect on genes involved in cholesterol homeostasis and evaluated their relationship with patients' survival in ACC TCGA. We then blocked cholesterol synthesis with simvastatin and determined the effects on H295R cell proliferation, estradiol production, and ERα activity in vitro and in xenograft tumors. We found that mitotane increases intratumor cholesterol content and expression of genes involved in cholesterol homeostasis, among them INSIG, whose expression affects patients' survival. Treatment of H295R cells with simvastatin to block cholesterol synthesis decreased cellular cholesterol content, and this affected cell viability. Simvastatin reduced estradiol production and decreased nuclear and mitochondrial ERα function. A mitochondrial target of ERα, the respiratory complex IV (COXIV), was reduced after simvastatin treatment, which profoundly affected mitochondrial respiration activating apoptosis. Additionally, simvastatin reduced tumor volume and weight of grafted H295R cells, intratumor cholesterol content, Ki-67 and ERα, COXIV expression and activity and increase terminal deoxynucleotidyl transferase dUTP nick end labeling–positive cells. Collectively, these data demonstrate that a reduction in intratumor cholesterol content prevents estradiol production and inhibits mitochondrial respiratory chain–inducing apoptosis in ACC cells. Inhibition of mitochondrial respiration by simvastatin represents a novel strategy to counteract ACC growth.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Mol Cancer Ther 2020;19:1909–21

  • Received November 13, 2019.
  • Revision received March 8, 2020.
  • Accepted June 11, 2020.
  • Published first June 16, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 19 (9)
September 2020
Volume 19, Issue 9
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Statins Reduce Intratumor Cholesterol Affecting Adrenocortical Cancer Growth
Francesca Trotta, Paola Avena, Adele Chimento, Vittoria Rago, Arianna De Luca, Sara Sculco, Marta C. Nocito, Rocco Malivindi, Francesco Fallo, Raffaele Pezzani, Catia Pilon, Francesco M. Lasorsa, Simona N. Barile, Luigi Palmieri, Antonio M. Lerario, Vincenzo Pezzi, Ivan Casaburi and Rosa Sirianni
Mol Cancer Ther September 1 2020 (19) (9) 1909-1921; DOI: 10.1158/1535-7163.MCT-19-1063

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Statins Reduce Intratumor Cholesterol Affecting Adrenocortical Cancer Growth
Francesca Trotta, Paola Avena, Adele Chimento, Vittoria Rago, Arianna De Luca, Sara Sculco, Marta C. Nocito, Rocco Malivindi, Francesco Fallo, Raffaele Pezzani, Catia Pilon, Francesco M. Lasorsa, Simona N. Barile, Luigi Palmieri, Antonio M. Lerario, Vincenzo Pezzi, Ivan Casaburi and Rosa Sirianni
Mol Cancer Ther September 1 2020 (19) (9) 1909-1921; DOI: 10.1158/1535-7163.MCT-19-1063
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