Prion-like nanofibrils of small molecules (PriSM) selectively inhibit cancer cells by impeding cytoskeleton dynamics.

Abstract

Emerging evidence reveals that prion-like structures play important roles to maintain the well-being of cells. Although self-assembly of small molecules also affords prion-like nanofibrils (PriSM), little is known about the functions and mechanisms of PriSM. Previous works demonstrated that PriSM formed by a dipeptide derivative selectively inhibiting the growth of glioblastoma cells over neuronal cells and effectively inhibiting xenograft tumor in animal models. 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.

• Authors: Yi Kuang, Marcus J C Long, Jie Zhou, Junfeng Shi, Yuan Gao, Chen Xu, Lizbeth Hedstrom, Bing Xu
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 289 Issue 42 Pg. 29208-18 (Oct 17 2014) ISSN: 1083-351X [Electronic] United States
• PMID: 25157102 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Antineoplastic Agents
• Peptides
• Prions
• Tubulin
• tau Proteins
• Paclitaxel
• Nocodazole

Topics

• Antineoplastic Agents (chemistry)
• Apoptosis
• Cytoskeleton (metabolism)
• Endocytosis
• Glioblastoma (drug therapy)
• HeLa Cells
• Hep G2 Cells
• Humans
• MCF-7 Cells
• Nanoparticles (chemistry)
• Nanotechnology
• Neoplasm Transplantation
• Neoplasms (metabolism)
• Nocodazole (chemistry)
• Paclitaxel (chemistry)
• Peptides (chemistry)
• Prions (chemistry)
• Protein Structure, Tertiary
• Tubulin (chemistry)
• tau Proteins (chemistry)