PP2A inhibitors suppress migration and growth of PANC-1 pancreatic cancer cells through inhibition on the Wnt/beta-catenin pathway by phosphorylation and degradation of beta-catenin

摘要

Cantharidin is an active constituent of mylabris, a traditional Chinese medicine, and presents strong anticancer activity in various cell lines. Cantharidin is a potent and selective inhibitor of serine/threonine protein phosphatase 2A (PP2A). Our previous studies revealed the prospect of application of cantharidin, as well as other PP2A inhibitors, in the treatment of pancreatic cancer. However, the mechanisms involved in the anticancer effect of PP2A inhibitors have not been fully explored. The Wnt/beta-catenin pathway is involved in cell migration and proliferation and participates in the progression of pancreatic cancer. If beta-catenin is phosphorylated and degraded, the Wnt/beta-catenin pathway is blocked. PP2A dephosphorylates beta-catenin and keeps the Wnt/beta-catenin pathway active. In the present study, we found that PP2A inhibitor treatment induced phosphorylation and degradation of beta-catenin. The suppression on the migration and growth of PANC-1 pancreatic cancer cells could be attenuated by pretreatment with FH535, a beta-catenin pathway inhibitor. Microarray showed that PP2A inhibitor treatment induced expression changes in 13 of 138 genes downstream of the beta-catenin pathway. Real-time PCR further confirmed that FH535 attenuated the expression changes induced by PP2A inhibitors in 6 of these 13 candidate genes. These 6 genes, VEGFB, Dkk3, KRT8, NRP1, Cacnalg and WISP2, have been confirmed to participate in the migration and/or growth regulation in previous studies. Thus, the phosphorylation- and degradation-mediated suppression on beta-catenin participates in the cytotoxicity of PP2A inhibitors. Our findings may provide insight into the treatment of pancreatic cancer using a targeting PP2A strategy.