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Repurposing atorvastatin for uterine leiomyosarcoma: mevalonate pathway inhibition yields preclinical antitumor
Fang-Liang Zhou1,2, Yi-Bin Wu2, Wen Wang2
1Department of Biochemistry & Molecular Biology, Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
Abstract:
Uterine leiomyosarcoma (ULMS) is a rare yet aggressive uterine malignancy with high recurrence and poor survival, prompting an urgent search for better treatments. We investigated whether atorvastatin, an HMG-CoA reductase inhibitor, could suppress ULMS growth by targeting mevalonate pathway-dependent prenylation. Human ULMS cell lines received atorvastatin ± isoprenoids to assess proliferation, cell-cycle distribution, and smooth muscle contractility, whereas proteomic profiling (LC-MS/MS) and in vivo xenografts were used to evaluate molecular pathways and antitumor efficacy. Atorvastatin inhibited ULMS proliferation in a dose-dependent manner, induced G₀/G₁ cell-cycle arrest, and diminished the contractile phenotype. Geranylgeranyl pyrophosphate rescued these effects, implicating geranylgeranylation as the key dependency, and Rap1A/Rap1B Western blotting confirmed functional GGPP depletion. In xenografts, atorvastatin suppressed ULMS tumor growth by ~50% with minimal toxicity, as evidenced by normal serum ALT and creatinine levels and preserved organ histology. These findings identify protein geranylgeranylation as a novel therapeutic vulnerability in ULMS and support statin repurposing as a promising treatment strategy.
Insights
Atorvastatin, a statin drug, effectively inhibits uterine leiomyosarcoma (ULMS) growth by blocking protein geranylgeranylation. This study supports repurposing statins as a promising new treatment strategy for this aggressive cancer.
Area of Science:
- Oncology
- Biochemistry
- Pharmacology
Background:
- Uterine leiomyosarcoma (ULMS) is an aggressive malignancy with poor prognosis.
- Current treatment options for ULMS are limited, necessitating novel therapeutic strategies.
Purpose of the Study:
- To investigate the efficacy of atorvastatin in suppressing ULMS growth.
- To explore the role of the mevalonate pathway and protein prenylation in ULMS pathogenesis.
- To evaluate atorvastatin's potential as a repurposed drug for ULMS treatment.
Main Methods:
- In vitro studies using human ULMS cell lines treated with atorvastatin and isoprenoids.
- Assessment of cell proliferation, cell-cycle distribution, and smooth muscle contractility.
- Proteomic profiling (LC-MS/MS) and in vivo xenograft models to evaluate antitumor efficacy and molecular pathways.
Main Results:
- Atorvastatin significantly inhibited ULMS cell proliferation and induced G₀/G₁ cell-cycle arrest.
- Geranylgeranyl pyrophosphate (GGPP) supplementation rescued atorvastatin-induced effects, highlighting geranylgeranylation as a key dependency.
- In vivo studies demonstrated that atorvastatin suppressed ULMS tumor growth by approximately 50% with minimal observed toxicity.
Conclusions:
- Protein geranylgeranylation is identified as a novel therapeutic vulnerability in ULMS.
- Repurposing statins, like atorvastatin, represents a promising treatment strategy for uterine leiomyosarcoma.
- Targeting the mevalonate pathway offers a potential avenue for improving ULMS outcomes.
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