Kim Myeong-Ok, Choe Min Ho, Yoon Yi Na, Ahn Jiyeon, Yoo Minjin, Jung Kwan-Young, An Sungkwan, Hwang Sang-Gu, Oh Jeong Su, Kim Jae-Sung
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.
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.
Biochem Pharmacol. 2017 Nov 15;144:78-89. doi: 10.1016/j.bcp.2017.08.009. Epub 2017 Aug 13.
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.
蛋白磷酸酶2A（PP2A）是一种关键的肿瘤抑制复合物，负责使各种癌基因失活。最近，PP2A再激活已成为一种抗癌策略。蛋白磷酸酶2A的癌性抑制剂（CIP2A）是PP2A的一种内源性抑制剂，在包括非小细胞肺癌（NSCLC）细胞在内的许多癌细胞中上调。我们证明，抗蠕虫药氯硝柳胺抑制CIP2A的表达，并使NSCLC细胞中的肿瘤抑制因子PP2A重新激活。我们进行了药物再利用筛选，并确定氯硝柳胺是NSCLC细胞中的一种CIP2A抑制剂。氯硝柳胺抑制NSCLC细胞的增殖、集落形成和肿瘤球形成，并通过增加线粒体活性氧的产生诱导线粒体功能障碍；然而，这些作用可通过CIP2A过表达得到挽救，这表明氯硝柳胺的抗肿瘤活性依赖于CIP2A。我们发现氯硝柳胺通过抑制CIP2A增加PP2A活性，从而减少几种致癌蛋白的磷酸化。此外，我们发现一种氯硝柳胺类似物在几种类型的NSCLC细胞中抑制CIP2A表达并增加PP2A活性。最后，我们表明其他著名的PP2A激活剂，包括福司可林和FTY720，不抑制CIP2A，并且它们的活性不依赖于CIP2A。总的来说，我们的数据表明氯硝柳胺有效地抑制了NSCLC细胞中CIP2A的表达，并随后激活了PP2A。这为氯硝柳胺作为PP2A激活药物在NSCLC临床治疗中的潜在应用提供了有力证据。
