Antihelminthic drug niclosamide inhibits CIP2A and reactivates tumor suppressor protein phosphatase 2A in non-small cell lung cancer cells
[Display omitted] Protein phosphatase 2A (PP2A) is a critical tumor suppressor complex responsible for the inactivation of various oncogenes. Recently, PP2A reactivation has emerged asan anticancer strategy. Cancerous inhibitor of protein phosphatase 2A (CIP2A), an endogenous inhibitor of PP2A, is u...
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Published in | Biochemical pharmacology Vol. 144; pp. 78 - 89 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
England
Elsevier Inc
15.11.2017
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Abstract | [Display omitted]
Protein phosphatase 2A (PP2A) is a critical tumor suppressor complex responsible for the inactivation of various oncogenes. Recently, PP2A reactivation has emerged asan anticancer strategy. Cancerous inhibitor of protein phosphatase 2A (CIP2A), an endogenous inhibitor of PP2A, is upregulated in many cancer cells, including non-small cell lung cancer (NSCLC) cells. We demonstrated that the antihelminthic drug niclosamide inhibited the expression of CIP2A and reactivated the tumor suppressor PP2A in NSCLC cells. We performed a drug-repurposing screen and identified niclosamide asa CIP2A suppressor in NSCLC cells. Niclosamide inhibited cell proliferation, colony formation, and tumor sphere formation, and induced mitochondrial dysfunction through increased mitochondrial ROS production in NSCLC cells; however, these effects were rescued by CIP2A overexpression, which indicated that the antitumor activity of niclosamide was dependent on CIP2A. We found that niclosamide increased PP2A activity through CIP2A inhibition, which reduced the phosphorylation of several oncogenic proteins. Moreover, we found that a niclosamide analog inhibited CIP2A expression and increased PP2A activity in several types of NSCLC cells. Finally, we showed that other well-known PP2A activators, including forskolin and FTY720, did not inhibit CIP2A and that their activities were not dependent on CIP2A. Collectively, our data suggested that niclosamide effectively suppressed CIP2A expression and subsequently activated PP2A in NSCLC cells. This provided strong evidence for the potential use of niclosamide asa PP2A-activating drug in the clinical treatment of NSCLC. |
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AbstractList | [Display omitted]
Protein phosphatase 2A (PP2A) is a critical tumor suppressor complex responsible for the inactivation of various oncogenes. Recently, PP2A reactivation has emerged asan anticancer strategy. Cancerous inhibitor of protein phosphatase 2A (CIP2A), an endogenous inhibitor of PP2A, is upregulated in many cancer cells, including non-small cell lung cancer (NSCLC) cells. We demonstrated that the antihelminthic drug niclosamide inhibited the expression of CIP2A and reactivated the tumor suppressor PP2A in NSCLC cells. We performed a drug-repurposing screen and identified niclosamide asa CIP2A suppressor in NSCLC cells. Niclosamide inhibited cell proliferation, colony formation, and tumor sphere formation, and induced mitochondrial dysfunction through increased mitochondrial ROS production in NSCLC cells; however, these effects were rescued by CIP2A overexpression, which indicated that the antitumor activity of niclosamide was dependent on CIP2A. We found that niclosamide increased PP2A activity through CIP2A inhibition, which reduced the phosphorylation of several oncogenic proteins. Moreover, we found that a niclosamide analog inhibited CIP2A expression and increased PP2A activity in several types of NSCLC cells. Finally, we showed that other well-known PP2A activators, including forskolin and FTY720, did not inhibit CIP2A and that their activities were not dependent on CIP2A. Collectively, our data suggested that niclosamide effectively suppressed CIP2A expression and subsequently activated PP2A in NSCLC cells. This provided strong evidence for the potential use of niclosamide asa PP2A-activating drug in the clinical treatment of NSCLC. Protein phosphatase 2A (PP2A) is a critical tumor suppressor complex responsible for the inactivation of various oncogenes. Recently, PP2A reactivation has emerged asan anticancer strategy. Cancerous inhibitor of protein phosphatase 2A (CIP2A), an endogenous inhibitor of PP2A, is upregulated in many cancer cells, including non-small cell lung cancer (NSCLC) cells. We demonstrated that the antihelminthic drug niclosamide inhibited the expression of CIP2A and reactivated the tumor suppressor PP2A in NSCLC cells. We performed a drug-repurposing screen and identified niclosamide asa CIP2A suppressor in NSCLC cells. Niclosamide inhibited cell proliferation, colony formation, and tumor sphere formation, and induced mitochondrial dysfunction through increased mitochondrial ROS production in NSCLC cells; however, these effects were rescued by CIP2A overexpression, which indicated that the antitumor activity of niclosamide was dependent on CIP2A. We found that niclosamide increased PP2A activity through CIP2A inhibition, which reduced the phosphorylation of several oncogenic proteins. Moreover, we found that a niclosamide analog inhibited CIP2A expression and increased PP2A activity in several types of NSCLC cells. Finally, we showed that other well-known PP2A activators, including forskolin and FTY720, did not inhibit CIP2A and that their activities were not dependent on CIP2A. Collectively, our data suggested that niclosamide effectively suppressed CIP2A expression and subsequently activated PP2A in NSCLC cells. This provided strong evidence for the potential use of niclosamide asa PP2A-activating drug in the clinical treatment of NSCLC. |
Author | Jung, Kwan-Young Yoon, Yi Na Ahn, Jiyeon Kim, Jae-Sung Oh, Jeong Su Yoo, Minjin Choe, Min Ho Hwang, Sang-Gu Kim, Myeong-ok An, Sungkwan |
Author_xml | – sequence: 1 givenname: Myeong-ok surname: Kim fullname: Kim, Myeong-ok organization: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea – sequence: 2 givenname: Min Ho surname: Choe fullname: Choe, Min Ho organization: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea – sequence: 3 givenname: Yi Na surname: Yoon fullname: Yoon, Yi Na organization: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea – sequence: 4 givenname: Jiyeon surname: Ahn fullname: Ahn, Jiyeon organization: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea – sequence: 5 givenname: Minjin surname: Yoo fullname: Yoo, Minjin organization: Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, South Korea – sequence: 6 givenname: Kwan-Young surname: Jung fullname: Jung, Kwan-Young organization: Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, South Korea – sequence: 7 givenname: Sungkwan surname: An fullname: An, Sungkwan organization: Molecular-Targeted Drug Research Center and Korea Institute for Skin and Clinical Sciences, Konkuk University, Seoul, South Korea – sequence: 8 givenname: Sang-Gu surname: Hwang fullname: Hwang, Sang-Gu organization: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea – sequence: 9 givenname: Jeong Su surname: Oh fullname: Oh, Jeong Su email: ohjs@skku.edu organization: Department of Genetic Engineering, Sungkyunkwan University, Suwon, South Korea – sequence: 10 givenname: Jae-Sung surname: Kim fullname: Kim, Jae-Sung email: jaesung@kirams.re.kr organization: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/28813646$$D View this record in MEDLINE/PubMed |
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Keywords | Niclosamide Drug repositioning Niclosamide (PubChem CID: 4477) Niclosamide analog 1 (PubChem CID: 71527596) PP2A Niclosamide analog 2 (PubChem CID: 25217158) CIP2A Non-small cell lung cancer cells |
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Protein phosphatase 2A (PP2A) is a critical tumor suppressor complex responsible for the inactivation of various oncogenes. Recently, PP2A... Protein phosphatase 2A (PP2A) is a critical tumor suppressor complex responsible for the inactivation of various oncogenes. Recently, PP2A reactivation has... |
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SubjectTerms | Anthelmintics - pharmacology Anthelmintics - therapeutic use Antinematodal Agents - pharmacology Antinematodal Agents - therapeutic use Autoantigens - metabolism Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - metabolism Cell Line, Tumor Cell Survival - drug effects Cell Survival - physiology CIP2A Dose-Response Relationship, Drug Drug repositioning Humans Lung Neoplasms - drug therapy Lung Neoplasms - metabolism Membrane Potential, Mitochondrial - drug effects Membrane Proteins - antagonists & inhibitors Membrane Proteins - metabolism Niclosamide Niclosamide - pharmacology Niclosamide - therapeutic use Non-small cell lung cancer cells PP2A Protein Phosphatase 2 - metabolism |
Title | Antihelminthic drug niclosamide inhibits CIP2A and reactivates tumor suppressor protein phosphatase 2A in non-small cell lung cancer cells |
URI | https://dx.doi.org/10.1016/j.bcp.2017.08.009 https://www.ncbi.nlm.nih.gov/pubmed/28813646 |
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