Abstract
Cheliensisin A (Chel A), a styryl-lactone compound extracted from Goniothalamus cheliensis, is reported to have significant anti-cancer effects in various cancer cells. Here we demonstrated that Chel A treatment resulted in apoptosis and an inhibition of anchorage-independent growth in human bladder cancer T24, T24T and U5637 cells. Mechanistic studies showed that such effect is mediated by PH domain and Leucine rich repeat Protein Phosphatases (PHLPP2) protein. Chel A treatment led to PHLPP2 degradation and subsequently increased in c-Jun phosphorylation. Moreover PHLPP2 degradation could be attenuated by inhibition of autophagy, which was mediated by Beclin 1. Collectively, we discover that Chel A treatment induces Beclin-dependent autophagy, consequently mediates PHLPP2 degradation and JNK/C-Jun phosphorylation and activation, further in turn contributing to apoptosis in human bladder cancer cells. Current studies provide a significant insight into understanding of anticancer effect of Chel A in treatment of human bladder cancer.
Highlights
Cheliensisin A (Chel A, GC-51) has drawn a lot of interest in the last decade because of its potential role as an anti-cancer drug
We discover that Chel A treatment induces Beclindependent autophagy, mediates PHLPP2 degradation and Jun NH2-Terminal Kinase (JNK)/C-Jun phosphorylation and activation, further in turn contributing to apoptosis in human bladder cancer cells
The results showed that anchorage-independent growth of T24T, U5637 and T24 were dramatically attenuated by Chel A in a dose-dependent manner (Figure 1B and 1C), suggesting anti-cancer activity of Chel A in human bladder cancer
Summary
Cheliensisin A (Chel A, GC-51) has drawn a lot of interest in the last decade because of its potential role as an anti-cancer drug. Previous studies reveal that Chel A has cytotoxicity against human leukemia cells via a PKA-dependent pathway by down-regulating Bcl-2 expression [1], the mechanism of Chel A’s anti-cancer effects remains largely unknown. We continued our efforts on Chel A’s anti-cancer properties for apoptotic induction in human bladder cancer cells. Bladder cancer is highly associated with environmental risk factors including smoking, poor nutrition and occupational exposure to various chemicals [4]. Because of such strong links to environmental risk factors, it is reasonable to use a natural chemical compounds to inhibit bladder cancer’s development. We used the T24T cell line, a highly metastatic variant of the T24 bladder cancer cell line [7], to test the chemotherapeutic effects and mechanistic action of Chel A
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