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Article

Simvastatin Induces Apoptosis in Medulloblastoma Brain Tumor Cells via Mevalonate Cascade Prenylation Substrates

1
Regenerative Medicine Program, Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, 745 Bannatyne Avenue, BMSB 627, Winnipeg, MB R3E 0J9, Canada
2
Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A1, Canada
3
Department of Human Anatomy and Cell Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
4
Research Institute of Oncology and Hematology, CancerCare Manitoba, Winnipeg, MB R3E 0V9, Canada
*
Author to whom correspondence should be addressed.
These authors equally contributed to this work.
Cancers 2019, 11(7), 994; https://doi.org/10.3390/cancers11070994
Received: 5 July 2019 / Accepted: 12 July 2019 / Published: 17 July 2019
(This article belongs to the Special Issue Apoptosis in Cancer)
Medulloblastoma is a common pediatric brain tumor and one of the main types of solid cancers in children below the age of 10. Recently, cholesterol-lowering “statin” drugs have been highlighted for their possible anti-cancer effects. Clinically, statins are reported to have promising potential for consideration as an adjuvant therapy in different types of cancers. However, the anti-cancer effects of statins in medulloblastoma brain tumor cells are not currently well-defined. Here, we investigated the cell death mechanisms by which simvastatin mediates its effects on different human medulloblastoma cell lines. Simvastatin is a lipophilic drug that inhibits HMG-CoA reductase and has pleotropic effects. Inhibition of HMG-CoA reductase prevents the formation of essential downstream intermediates in the mevalonate cascade, such as farnesyl pyrophosphate (FPP) and gernaylgerany parophosphate (GGPP). These intermediates are involved in the activation pathway of small Rho GTPase proteins in different cell types. We observed that simvastatin significantly induces dose-dependent apoptosis in three different medulloblastoma brain tumor cell lines (Daoy, D283, and D341 cells). Our investigation shows that simvastatin-induced cell death is regulated via prenylation intermediates of the cholesterol metabolism pathway. Our results indicate that the induction of different caspases (caspase 3, 7, 8, and 9) depends on the nature of the medulloblastoma cell line. Western blot analysis shows that simvastatin leads to changes in the expression of regulator proteins involved in apoptosis, such as Bax, Bcl-2, and Bcl-xl. Taken together, our data suggests the potential application of a novel non-classical adjuvant therapy for medulloblastoma, through the regulation of protein prenylation intermediates that occurs via inhibition of the mevalonate pathway. View Full-Text
Keywords: medulloblastoma; brain tumor; apoptosis; mevalonate cascade inhibition; simvastatin medulloblastoma; brain tumor; apoptosis; mevalonate cascade inhibition; simvastatin
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MDPI and ACS Style

Sheikholeslami, K.; Ali Sher, A.; Lockman, S.; Kroft, D.; Ganjibakhsh, M.; Nejati-Koshki, K.; Shojaei, S.; Ghavami, S.; Rastegar, M. Simvastatin Induces Apoptosis in Medulloblastoma Brain Tumor Cells via Mevalonate Cascade Prenylation Substrates. Cancers 2019, 11, 994. https://doi.org/10.3390/cancers11070994

AMA Style

Sheikholeslami K, Ali Sher A, Lockman S, Kroft D, Ganjibakhsh M, Nejati-Koshki K, Shojaei S, Ghavami S, Rastegar M. Simvastatin Induces Apoptosis in Medulloblastoma Brain Tumor Cells via Mevalonate Cascade Prenylation Substrates. Cancers. 2019; 11(7):994. https://doi.org/10.3390/cancers11070994

Chicago/Turabian Style

Sheikholeslami, Kimia, Annan Ali Sher, Sandhini Lockman, Daniel Kroft, Meysam Ganjibakhsh, Kazem Nejati-Koshki, Shahla Shojaei, Saeid Ghavami, and Mojgan Rastegar. 2019. "Simvastatin Induces Apoptosis in Medulloblastoma Brain Tumor Cells via Mevalonate Cascade Prenylation Substrates" Cancers 11, no. 7: 994. https://doi.org/10.3390/cancers11070994

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