Atorvastatin Exerts Antileukemia Activity via Inhibiting Mevalonate-YAP Axis in K562 and HL60 Cells
Novel therapeutic strategies are still urgently expected for leukemia despite undisputed success of various targeted therapeutics. The antileukemia activity of Atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on human leukemia cells was investigated. Atorvastatin...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2019-10-01
|
| Series: | Frontiers in Oncology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fonc.2019.01032/full |
| _version_ | 1818408246707224576 |
|---|---|
| author | Lei Zhang Ting Chen Yonghai Dou Shaolu Zhang Shaolu Zhang Hongyan Liu Tungalagtamir Khishignyam Xiaofei Li Duo Zuo Zhe Zhang Meihua Jin Ran Wang Yuling Qiu YuXu Zhong Dexin Kong Dexin Kong |
| author_facet | Lei Zhang Ting Chen Yonghai Dou Shaolu Zhang Shaolu Zhang Hongyan Liu Tungalagtamir Khishignyam Xiaofei Li Duo Zuo Zhe Zhang Meihua Jin Ran Wang Yuling Qiu YuXu Zhong Dexin Kong Dexin Kong |
| author_sort | Lei Zhang |
| collection | DOAJ |
| description | Novel therapeutic strategies are still urgently expected for leukemia despite undisputed success of various targeted therapeutics. The antileukemia activity of Atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on human leukemia cells was investigated. Atorvastatin inhibited K562 and HL60 cell proliferation, induced G2/M cell cycle arrest in K562 cells by down-regulating cyclinB1 and cdc2, but G0/G1 arrest in HL60 cells by up-regulating p27 and down-regulating cyclinD1 and p-pRb. Atorvastatin also induced apoptosis in both cell lines, in which the reactive oxygen species (ROS)-related mitochondrial apoptotic signaling might be involved, with increase of ROS and Bax/Bcl-2 ratio, loss of mitochondrial membrane potential (MMP), release of cytochrome C into cytosol, and activation of Bax/Caspase-9/Caspase-3/PARP pathway. Inhibition of YAP nuclear localization and activation by Atorvastatin was reversed by the addition of mevalonate, GGPP, or FPP. Further, the effects on cell cycle arrest- and apoptosis- related proteins by Atorvastatin were alleviated by addition of mevalonate, suggesting the antileukemia effect of Atorvastatin might be through mevalonate-YAP axis in K562 and HL60 cells. Our results suggest that Atorvastatin might be used for leukemia therapy while evidence of clinical efficacy is required. |
| first_indexed | 2024-12-14T09:40:41Z |
| format | Article |
| id | doaj.art-90ed33487d3d4e5c82fe0639811126e4 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-14T09:40:41Z |
| publishDate | 2019-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-90ed33487d3d4e5c82fe0639811126e42022-12-21T23:07:47ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2019-10-01910.3389/fonc.2019.01032484028Atorvastatin Exerts Antileukemia Activity via Inhibiting Mevalonate-YAP Axis in K562 and HL60 CellsLei Zhang0Ting Chen1Yonghai Dou2Shaolu Zhang3Shaolu Zhang4Hongyan Liu5Tungalagtamir Khishignyam6Xiaofei Li7Duo Zuo8Zhe Zhang9Meihua Jin10Ran Wang11Yuling Qiu12YuXu Zhong13Dexin Kong14Dexin Kong15Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, ChinaTianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, ChinaTianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, ChinaTianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, ChinaState Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, ChinaState Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, ChinaTianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, ChinaTianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, ChinaTianjin Medical University Cancer Hospital, Tianjin, ChinaTianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, ChinaTianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, ChinaTianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, ChinaTianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, ChinaState Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, ChinaTianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, ChinaSchool of Medicine, Tianjin Tianshi College, Tianyuan University, Tianjin, ChinaNovel therapeutic strategies are still urgently expected for leukemia despite undisputed success of various targeted therapeutics. The antileukemia activity of Atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on human leukemia cells was investigated. Atorvastatin inhibited K562 and HL60 cell proliferation, induced G2/M cell cycle arrest in K562 cells by down-regulating cyclinB1 and cdc2, but G0/G1 arrest in HL60 cells by up-regulating p27 and down-regulating cyclinD1 and p-pRb. Atorvastatin also induced apoptosis in both cell lines, in which the reactive oxygen species (ROS)-related mitochondrial apoptotic signaling might be involved, with increase of ROS and Bax/Bcl-2 ratio, loss of mitochondrial membrane potential (MMP), release of cytochrome C into cytosol, and activation of Bax/Caspase-9/Caspase-3/PARP pathway. Inhibition of YAP nuclear localization and activation by Atorvastatin was reversed by the addition of mevalonate, GGPP, or FPP. Further, the effects on cell cycle arrest- and apoptosis- related proteins by Atorvastatin were alleviated by addition of mevalonate, suggesting the antileukemia effect of Atorvastatin might be through mevalonate-YAP axis in K562 and HL60 cells. Our results suggest that Atorvastatin might be used for leukemia therapy while evidence of clinical efficacy is required.https://www.frontiersin.org/article/10.3389/fonc.2019.01032/fullAtorvastatinanti-leukemiamevalonate-YAP axiscell cycleapoptosis |
| spellingShingle | Lei Zhang Ting Chen Yonghai Dou Shaolu Zhang Shaolu Zhang Hongyan Liu Tungalagtamir Khishignyam Xiaofei Li Duo Zuo Zhe Zhang Meihua Jin Ran Wang Yuling Qiu YuXu Zhong Dexin Kong Dexin Kong Atorvastatin Exerts Antileukemia Activity via Inhibiting Mevalonate-YAP Axis in K562 and HL60 Cells Frontiers in Oncology Atorvastatin anti-leukemia mevalonate-YAP axis cell cycle apoptosis |
| title | Atorvastatin Exerts Antileukemia Activity via Inhibiting Mevalonate-YAP Axis in K562 and HL60 Cells |
| title_full | Atorvastatin Exerts Antileukemia Activity via Inhibiting Mevalonate-YAP Axis in K562 and HL60 Cells |
| title_fullStr | Atorvastatin Exerts Antileukemia Activity via Inhibiting Mevalonate-YAP Axis in K562 and HL60 Cells |
| title_full_unstemmed | Atorvastatin Exerts Antileukemia Activity via Inhibiting Mevalonate-YAP Axis in K562 and HL60 Cells |
| title_short | Atorvastatin Exerts Antileukemia Activity via Inhibiting Mevalonate-YAP Axis in K562 and HL60 Cells |
| title_sort | atorvastatin exerts antileukemia activity via inhibiting mevalonate yap axis in k562 and hl60 cells |
| topic | Atorvastatin anti-leukemia mevalonate-YAP axis cell cycle apoptosis |
| url | https://www.frontiersin.org/article/10.3389/fonc.2019.01032/full |
| work_keys_str_mv | AT leizhang atorvastatinexertsantileukemiaactivityviainhibitingmevalonateyapaxisink562andhl60cells AT tingchen atorvastatinexertsantileukemiaactivityviainhibitingmevalonateyapaxisink562andhl60cells AT yonghaidou atorvastatinexertsantileukemiaactivityviainhibitingmevalonateyapaxisink562andhl60cells AT shaoluzhang atorvastatinexertsantileukemiaactivityviainhibitingmevalonateyapaxisink562andhl60cells AT shaoluzhang atorvastatinexertsantileukemiaactivityviainhibitingmevalonateyapaxisink562andhl60cells AT hongyanliu atorvastatinexertsantileukemiaactivityviainhibitingmevalonateyapaxisink562andhl60cells AT tungalagtamirkhishignyam atorvastatinexertsantileukemiaactivityviainhibitingmevalonateyapaxisink562andhl60cells AT xiaofeili atorvastatinexertsantileukemiaactivityviainhibitingmevalonateyapaxisink562andhl60cells AT duozuo atorvastatinexertsantileukemiaactivityviainhibitingmevalonateyapaxisink562andhl60cells AT zhezhang atorvastatinexertsantileukemiaactivityviainhibitingmevalonateyapaxisink562andhl60cells AT meihuajin atorvastatinexertsantileukemiaactivityviainhibitingmevalonateyapaxisink562andhl60cells AT ranwang atorvastatinexertsantileukemiaactivityviainhibitingmevalonateyapaxisink562andhl60cells AT yulingqiu atorvastatinexertsantileukemiaactivityviainhibitingmevalonateyapaxisink562andhl60cells AT yuxuzhong atorvastatinexertsantileukemiaactivityviainhibitingmevalonateyapaxisink562andhl60cells AT dexinkong atorvastatinexertsantileukemiaactivityviainhibitingmevalonateyapaxisink562andhl60cells AT dexinkong atorvastatinexertsantileukemiaactivityviainhibitingmevalonateyapaxisink562andhl60cells |