Mevalonate Cascade Inhibition by Simvastatin Induces the Intrinsic Apoptosis Pathway via Depletion of Isoprenoids in Tumor Cells

Alizadeh, Javad; Zeki, Amir A.; Mirzaei, Nima; Tewary, Sandipan; Moghadam, Adel Rezaei; Głogowska, Aleksandra; Nagakannan, Pandian; Eftekharpour, Eftekhar; Wiecheć, Emilia; Gordon, Joseph W.; Xu, Fred Y.; Field, Jared T.; Yoneda, Ken Y.; Kenyon, Nicholas J.; Hashemi, Mohammad; Hatch, Grant M.; Hombach‐Klonisch, Sabine; Klonisch, Thomas; Ghavami, Saeid

doi:10.1038/srep44841

Cited by 116 publications

(126 citation statements)

References 93 publications

(110 reference statements)

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“…In these studies, INS-1 832/13 cells were incubated in the absence (diluent]) or presence of simvastatin (0-30 µM) and FTI-277 (15 µM) for different time intervals as described in the text. Earlier studies have demonstrated that both of these agents, in the stated concentration range, significantly inhibited MVA and protein prenylation pathways in a variety of cells, including the islet β-cell [16, 17, 19-22]. …”

Section: Methodsmentioning

confidence: 99%

Inhibition of Prenylation Promotes Caspase 3 Activation, Lamin B Degradation and Loss in Metabolic Cell Viability in Pancreatic β-Cells

Syeda¹,

Kowluru²

2017

Cell Physiol Biochem

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Background/Aims: Lamins are intermediate filament proteins that constitute the main components of the lamina underlying the inner-nuclear membrane and serve to organize chromatin. Lamins (e.g., lamin B) undergo posttranslational modifications (e.g., isoprenylation) at their C-terminal cysteine residues. Such modifications are thought to render optimal association of lamins with the nuclear envelop. Using human islets, rodent islets, and INS-1 832/13 cells, we recently reported significant metabolic defects under glucotoxic and endoplasmic reticulum (ER) stress conditions, including caspase 3 activation and lamin B degradation. The current study is aimed at further understanding the regulatory roles of protein prenylation in the induction of the aforestated metabolic defects. Methods: Subcellular phase partitioning assay was done using Triton X-114. Cell morphology and metabolic cell viability assays were carried out using standard methodologies. Results: We report that exposure of pancreatic β-cells to Simvastatin, an inhibitor of mevalonic acid (MVA) biosynthesis, and its downstream isoprenoid derivatives, or FTI-277, an inhibitor of farnesyltransferase that mediates farnesylation of lamins, leads to activation of caspase 3 and lamin B degradation. Furthermore, Simvastatin-treatment increased activation of p38MAPK (a stress kinase) and inhibited ERK1/2 (regulator of cell proliferation). Inhibition of farnesylation also resulted in the release of degraded lamin B into the cytosolic fraction and promoted loss in metabolic cell viability. Conclusion: Based on these findings we conclude that protein prenylation plays key roles in islet β-cell function. These findings affirm further support to the hypothesis that defects in prenylation pathway induce caspase-3 activation and nuclear lamin degradation in pancreatic β-cells under the duress of metabolic stress (e.g., glucotoxicity).

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Section: Methodsmentioning

confidence: 99%

Inhibition of Prenylation Promotes Caspase 3 Activation, Lamin B Degradation and Loss in Metabolic Cell Viability in Pancreatic β-Cells

Syeda¹,

Kowluru²

2017

Cell Physiol Biochem

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“…In addition to a wide range of tumor cells, we have shown that Simva (10 lM) induces cell death in primary human airway mesenchymal cells and primary human atrial fibroblasts via the intrinsic apoptotic pathway [20,29,67]. In GBM cells, we show that Simva, TMZ, and Simva/TMZ combination induced intrinsic apoptotic cell death, with Simva/TMZ inducing significantly more apoptosis when compared to the singular treatments ( Fig.…”

mentioning

confidence: 74%

Simvastatin increases temozolomide‐induced cell death by targeting the fusion of autophagosomes and lysosomes

et al. 2019

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Temozolomide (TMZ) is a chemotherapy agent used to treat Grade IV astrocytoma, also known as glioblastoma (GBM). TMZ treatment causes DNA damage that results in tumor cell apoptosis and increases the survival rate of GBM patients. However, chemoresistance as a result of TMZ‐induced autophagy significantly reduces this anticancer effects over time. Statins are competitive inhibitors of HMG‐CoA reductase, the rate‐limiting enzyme of the mevalonate (MEV) cascade. Statins are best known for their cholesterol (CH)‐lowering effect. Long‐term consumption of statins, prior to and in parallel with other cancer therapeutic approaches, has been reported to increase the survival rate of patients with various forms of cancers. In this study, we investigated the potentiation of TMZ‐induced apoptosis by simvastatin (Simva) in human GBM cell lines and patient GBM cells, using cell monolayers and three‐dimensional cell culture systems. The incubation of cells with a combination of Simva and TMZ resulted in a significant increase in apoptotic cells compared to cells treated with TMZ alone. Incubation of cells with CH or MEV cascade intermediates failed to compensate the decrease in cell viability induced by the combined Simva and TMZ treatment. Simva treatment inhibited the autophagy flux induced by TMZ by blocking autophago‐lysosome formation. Our results suggest that Simva sensitizes GBM cells to TMZ‐induced cell death in a MEV cascade‐independent manner and identifies the inhibition of autophagosome‐lysosome fusion as a promising therapeutic strategy in the treatment of GBM.

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“…In line with our findings, Yanae et al 55 showed that statins inhibit cell proliferation and increase caspase-3 activity indicating apoptosis in C6 glioma cells. These effects were reversed by the addition of GGPP but not FPP 7. A cohort study evaluated the influence of simvastatin use on survival of 339 patients with GBM and showed that long-term prediagnostic statin use may improve survival following GBM (a reduced HR of death (0.79; 95% CI 0.63 to 1.00)).…”

Section: Statins and Gbm Cancer Therapymentioning

confidence: 99%

Statins: A New Approach to Combat Temozolomide Chemoresistance in Glioblastoma

Shojaei

Alizadeh

Thliveris

et al. 2018

Journal of Investigative Medicine

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Patients with glioblastoma multiforme (GBM) have an average life expectancy of approximately 15 months. Recently, statins have emerged as a potential adjuvant cancer therapy due to their ability to inhibit cell proliferation and induce apoptosis in many types of cancer. The exact mechanisms that mediate the inhibitory actions of statins in cancer cells are largely unknown. The purpose of this proceeding paper is to discuss some of the known anticancer effects of statins, while focusing on GBM therapy that includes adjunct therapy of statins with chemotherapeutic agents.

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Mevalonate Cascade Inhibition by Simvastatin Induces the Intrinsic Apoptosis Pathway via Depletion of Isoprenoids in Tumor Cells

Cited by 116 publications

References 93 publications

Inhibition of Prenylation Promotes Caspase 3 Activation, Lamin B Degradation and Loss in Metabolic Cell Viability in Pancreatic β-Cells

Inhibition of Prenylation Promotes Caspase 3 Activation, Lamin B Degradation and Loss in Metabolic Cell Viability in Pancreatic β-Cells

Simvastatin increases temozolomide‐induced cell death by targeting the fusion of autophagosomes and lysosomes

Statins: A New Approach to Combat Temozolomide Chemoresistance in Glioblastoma

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