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Abstract
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 information

Kim MO1, Choe MH2, Yoon YN3, Ahn J4, Yoo M5, Jung KY6, An S7, Hwang SG4, Oh JS8, Kim JS9.
1
Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea; Molecular-Targeted Drug Research Center and Korea Institute for Skin and Clinical Sciences, Konkuk University, Seoul, South Korea.
2
Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea; Department of Life Sciences and Biotechnology, College of Life Science and Biotechnology, Korea University, Seoul, South Korea.
3
Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea; Radiological and Medico-Oncological Sciences, University of Science and Technology, South Korea.
4
Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea.
5
Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, South Korea.
6
Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, South Korea; Center for Medicinal Chemistry, Korea Research Institute of Chemical Technology, Daejeon, South Korea.
7
Molecular-Targeted Drug Research Center and Korea Institute for Skin and Clinical Sciences, Konkuk University, Seoul, South Korea.
8
Department of Genetic Engineering, Sungkyunkwan University, Suwon, South Korea. Electronic address: ohjs@skku.edu.
9
Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea; Radiological and Medico-Oncological Sciences, University of Science and Technology, South Korea. Electronic address: jaesung@kirams.re.kr.