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J Biol Chem. 2014 Oct 17;289(42):29208-18. doi: 10.1074/jbc.M114.600288. Epub 2014 Aug 25.

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

Author information

1
From the Department of Chemistry.
2
Graduate Program in Biochemistry and Biophysics.
3
Rosenstiel Basic Medical Sciences Research Center, and.
4
From the Department of Chemistry, Department of Biology, Brandeis University, Waltham, Massachusetts 02454.
5
From the Department of Chemistry, bxu@brandeis.edu.

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.

KEYWORDS:

Aggregation; Anticancer Drug; Apoptosis; Cancer; Nanotechnology

PMID:
25157102
PMCID:
PMC4200273
DOI:
10.1074/jbc.M114.600288
[Indexed for MEDLINE]
Free PMC Article

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