Antihelminthic drug niclosamide inhibits CIP2A and reactivates tumor suppressor protein phosphatase 2A in non-small cell lung cancer cells

Abstract Protein phosphatase 2A (PP2A) is a critical tumor suppressor complex responsiblefor the inactivation of various oncogenes. Recently, PP2A reactivation has emerged as an 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 niclosamideinhibited the expression of CIP2A and reactivated the tumor suppressor PP2A in NSCLC cells. We performed a drug- repurposingscreen and identified niclosamideas a CIP2A suppressor in NSCLC cells. Niclosamideinhibited cell proliferation, colony formation, and tumor sphere formation, and induced mitochondrial dysfunction through increased mitochondrial ROSproduction in NSCLC cells; however, these effects were rescued by CIP2A overexpression, which indicated that the antitumor activity of niclosamidewas dependent on CIP2A. We found that niclosamideincreased PP2A activity through CIP2A inhibition, which reduced the phosphorylation of several oncogenic proteins. Moreover, we found that a niclosamideanalog 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 niclosamideeffectively suppressed CIP2A expression and subsequently activated PP2A in NSCLC cells. This provided strong evidence for the potential use of niclosamideas a PP2A-activating drug in the clinical treatment of NSCLC.