Associate Professor City University of Hong Kong, Hong Kong
Jianbo Yue (City University of Hong Kong)
Metastasis is the fundamental cause of cancer mortality, but there are still very few anti-metastatic drugs available. Endosomal trafficking has been implicated in tumor metastasis, and we have recently identified several 6-morpholino-1,3,5-triazine derivatives, including vacuolin-1 (V1), as being inhibitors of this process. Here, we assessed the anti-metastatic activity of V1 both in vitro and in vivo. V1 significantly inhibits colony formation, migration, and invasion of various cancer cells in vitro. It also compromises the assembly-disassembly dynamics of focal adhesions (FAs) by inhibiting the recycling and degradation of integrins. In various experimental or transgenic mouse models, V1 significantly suppresses the metastasis and/or tumor growth of breast cancer or melanoma. We further identified capping protein Zβ (CapZβ) as a V1 binding protein, and showed that it is required for the V1-mediated inhibition of migration and metastasis of cancer cells. Collectively, our results indicate that 6-morpholino-1,3,5-triazine derivatives target CapZβ to inhibit endosomal trafficking and metastasis, and suggest that CapZβ is a potential therapeutic target against metastasis.
Model of how V1 targets CapZβ to inhibit endosomal trafficking and metastasis