Prion-like Nanofibrils of Small Molecules (PriSM) Selectively Inhibit Cancer Cells by Impeding Cytoskeleton Dynamics [Developmental Biology]

August 25th, 2014 by Kuang, Y., Long, M. J. C., Zhou, J., Shi, J., Gao, Y., Xu, C., Hedstrom, L., Xu, B.

Emerging evidence reveals that prion-like structures play important roles to maintain the well-being of cells. While self-assembly of small molecules also afford prion-like nanofibrils (PriSM), little is known on the functions and mechanisms of PriSM. Previous works demonstrated that PriSM formed by a dipeptide derivative selectively inhibit the growth of glioblastoma cells over neuronal cells and effectively inhibit xenograft tumor in animal model. Here we examine the protein targets, the internalization, and the cytotoxicity pathway of the PriSM. The results show that the PriSM selectively accumulate in cancer cells via macropinocytosis to impede the dynamics of cytoskeletal filaments via promiscuous interactions with cytoskeletal proteins, thus inducing apoptosis. Intriguingly, tau proteins are able to alleviate the effect of the PriSM, thus protecting neuronal cells. This work illustrates PriSM as a new paradigm for developing polypharmacological agents that promiscuously interact with multiple proteins yet result in a primary phenotype, such as cancer inhibition.