Statins Induce Cell Apoptosis Through a Modulation of AKT/FOXO1 Pathway in Prostate Cancer Cells

Overview

Journal Cancer Manag Res

Publisher Dove Medical Press

Specialty Oncology

Date 2019 Dec 17

PMID 31839714

Citations 18

Authors

Jun-Li Deng

Rui Zhang

Ying Zeng

Yuan-Shan Zhu

Guo Wang

Affiliations

Soon will be listed here.

Abstract

Background: In recent years, statins have been frequently investigated in neoplasms. However, the potential roles of statins on prostate cancer cells and the underlying mechanisms have not been fully elucidated. In current study, we explored the effect and molecular mechanism of statins on cell proliferation and apoptosis in prostate cancer cells.

Methods: Prostate cancer cell were treated with gradient doses of simvastatin and fluvastatin for 24-72 h. Cell proliferation was analyzed by using MTS assay and colony formation. Cell apoptosis was measured by Hoechst staining, ﬂow cytometry and caspase-3 activity. Western blotting was used to evaluate the proteins levels.

Results: Both simvastatin and fluvastatin produced a dose- and time-dependent inhibition of cell viability and colony formation while a promotion of cell apoptosis as evident with increases in caspase-3 activity, cleaved-caspase-3, cleaved-caspase-8 and cleaved-PARP levels in PC3 cells. Similar statin effects were observed in DU145 prostate cancer cells. Furthermore, statins produced a time- and dose-dependent reduction of phosphorylated-AKT and phosphorylated-FOXO1 levels in PC3 cells, and pretreatment of cells with an AKT phosphorylation inhibitor, MK2206, potentiated statins' effect.

Conclusion: Statins decrease cell proliferation and induce cell apoptosis, probably mediated via a downregulation of AKT/FOXO1 phosphorylation in prostate cancer cells, which may have a potential benefit in prostate cancer prevention and therapy.

Citing Articles

CARD16 restores tumorigenesis and restraints apoptosis in glioma cells Via FOXO1/TRAIL axis.

Xuan R, Hu T, Cai L, Zhao B, Han E, Xia Z Cell Death Dis. 2024; 15(11):804.

PMID: 39516471 PMC: 11549220. DOI: 10.1038/s41419-024-07196-2.

Erianin inhibits the progression of pancreatic cancer by directly targeting AKT and ASK1.

Liu R, Qiu M, Deng X, Zhang M, Gao Z, Wang Y Cancer Cell Int. 2024; 24(1):348.

PMID: 39456094 PMC: 11515188. DOI: 10.1186/s12935-024-03533-9.

Statins as anti-tumor agents: A paradigm for repurposed drugs.

Tripathi S, Gupta E, Galande S Cancer Rep (Hoboken). 2024; 7(5):e2078.

PMID: 38711272 PMC: 11074523. DOI: 10.1002/cnr2.2078.

Statin use and mortality risk in Asian patients with prostate cancer receiving androgen deprivation therapy: A population-based cohort study.

Lee Y, Chan J, Hui J, Tang P, Liu K, Dee E Cancer Med. 2023; 13(1):e6826.

PMID: 38140773 PMC: 10807587. DOI: 10.1002/cam4.6826.

Repositioning of HMG-CoA Reductase Inhibitors as Adjuvants in the Modulation of Efflux Pump-Mediated Bacterial and Tumor Resistance.

Schelz Z, Muddather H, Zupko I Antibiotics (Basel). 2023; 12(9).

PMID: 37760764 PMC: 10525194. DOI: 10.3390/antibiotics12091468.

References

Matusewicz L, Meissner J, Toporkiewicz M, Sikorski A . The effect of statins on cancer cells--review. Tumour Biol. 2015; 36(7):4889-904. DOI: 10.1007/s13277-015-3551-7. View

Gelmann E . Molecular biology of the androgen receptor. J Clin Oncol. 2002; 20(13):3001-15. DOI: 10.1200/JCO.2002.10.018. View

Hu M, Lee D, Xia W, Golfman L, Ou-Yang F, Yang J . IkappaB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell. 2004; 117(2):225-37. DOI: 10.1016/s0092-8674(04)00302-2. View

Zhang X, Tang N, Hadden T, Rishi A . Akt, FoxO and regulation of apoptosis. Biochim Biophys Acta. 2011; 1813(11):1978-86. DOI: 10.1016/j.bbamcr.2011.03.010. View

Yang J, Ning J, Peng L, He D . Effect of curcumin on Bcl-2 and Bax expression in nude mice prostate cancer. Int J Clin Exp Pathol. 2015; 8(8):9272-8. PMC: 4583908. View

Zheng D, Zhu G, Liao S, Yi W, Luo G, He J . Dysregulation of the PI3K/Akt signaling pathway affects cell cycle and apoptosis of side population cells in nasopharyngeal carcinoma. Oncol Lett. 2015; 10(1):182-188. PMC: 4487176. DOI: 10.3892/ol.2015.3218. View

Lopiccolo J, Blumenthal G, Bernstein W, Dennis P . Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations. Drug Resist Updat. 2008; 11(1-2):32-50. PMC: 2442829. DOI: 10.1016/j.drup.2007.11.003. View

Galili N, Davis R, Fredericks W, Mukhopadhyay S, Rauscher 3rd F, Emanuel B . Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma. Nat Genet. 1993; 5(3):230-5. DOI: 10.1038/ng1193-230. View

Zaballos M, Santisteban P . FOXO1 controls thyroid cell proliferation in response to TSH and IGF-I and is involved in thyroid tumorigenesis. Mol Endocrinol. 2012; 27(1):50-62. PMC: 5416949. DOI: 10.1210/me.2012-1032. View

10.

Burgering B, Kops G . Cell cycle and death control: long live Forkheads. Trends Biochem Sci. 2002; 27(7):352-60. DOI: 10.1016/s0968-0004(02)02113-8. View

11.

Zhu G, Yu C, She L, Tan H, Li G, Ren S . Metadherin regulation of vascular endothelial growth factor expression is dependent upon the PI3K/Akt pathway in squamous cell carcinoma of the head and neck. Medicine (Baltimore). 2015; 94(6):e502. PMC: 4602746. DOI: 10.1097/MD.0000000000000502. View

12.

Accili D, Arden K . FoxOs at the crossroads of cellular metabolism, differentiation, and transformation. Cell. 2004; 117(4):421-6. DOI: 10.1016/s0092-8674(04)00452-0. View

13.

Harshman L, Wang X, Nakabayashi M, Xie W, Valenca L, Werner L . Statin Use at the Time of Initiation of Androgen Deprivation Therapy and Time to Progression in Patients With Hormone-Sensitive Prostate Cancer. JAMA Oncol. 2015; 1(4):495-504. PMC: 5554437. DOI: 10.1001/jamaoncol.2015.0829. View

14.

Palacios F, Prieto D, Abreu C, Ruiz S, Morande P, Fernandez-Calero T . Dissecting chronic lymphocytic leukemia microenvironment signals in patients with unmutated disease: microRNA-22 regulates phosphatase and tensin homolog/AKT/FOXO1 pathway in proliferative leukemic cells. Leuk Lymphoma. 2014; 56(5):1560-5. DOI: 10.3109/10428194.2014.990900. View

15.

Zheng W, Wang H, Zeng Z, Lin J, Little P, Srivastava L . The possible role of the Akt signaling pathway in schizophrenia. Brain Res. 2012; 1470:145-58. DOI: 10.1016/j.brainres.2012.06.032. View

16.

Goc A, Kochuparambil S, Al-Husein B, Al-Azayzih A, Mohammad S, Somanath P . Simultaneous modulation of the intrinsic and extrinsic pathways by simvastatin in mediating prostate cancer cell apoptosis. BMC Cancer. 2012; 12:409. PMC: 3522038. DOI: 10.1186/1471-2407-12-409. View

17.

Petrylak D . New paradigms for advanced prostate cancer. Rev Urol. 2007; 9 Suppl 2:S3-S12. PMC: 1887815. View

18.

Fulda S, Debatin K . Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy. Oncogene. 2006; 25(34):4798-811. DOI: 10.1038/sj.onc.1209608. View

19.

Raval A, Thakker D, Negi H, Vyas A, Kaur H, Salkini M . Association between statins and clinical outcomes among men with prostate cancer: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis. 2016; 19(2):151-62. DOI: 10.1038/pcan.2015.58. View

20.

Platz E, Leitzmann M, Visvanathan K, Rimm E, Stampfer M, Willett W . Statin drugs and risk of advanced prostate cancer. J Natl Cancer Inst. 2006; 98(24):1819-25. DOI: 10.1093/jnci/djj499. View