title: 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.affiliation: From the Department of Chemistry.
authors.forename: Yi
authors.initials: Y
authors.lastname: Kuang
authors.affiliation: Graduate Program in Biochemistry and Biophysics.
authors.forename: Marcus J C
authors.initials: MJ
authors.lastname: Long
authors.affiliation: From the Department of Chemistry.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.affiliation: From the Department of Chemistry.
authors.forename: Junfeng
authors.initials: J
authors.lastname: Shi
authors.affiliation: From the Department of Chemistry.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Rosenstiel Basic Medical Sciences Research Center, and.
authors.forename: Chen
authors.initials: C
authors.lastname: Xu
authors.affiliation: From the Department of Chemistry, Department of Biology, Brandeis University, Waltham, Massachusetts 02454.
authors.forename: Lizbeth
authors.initials: L
authors.lastname: Hedstrom
authors.affiliation: From the Department of Chemistry, bxu@brandeis.edu.
authors.forename: Bing
authors.initials: B
authors.lastname: Xu
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry; D017209:Apoptosis; D003599:Cytoskeleton / Q000378:metabolism*; D004705:Endocytosis; D005909:Glioblastoma / Q000188:drug therapy; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D061986:MCF-7 Cells; D053758:Nanoparticles / Q000737:chemistry*; D036103:Nanotechnology; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism*; D015739:Nocodazole / Q000737:chemistry; D017239:Paclitaxel / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D011328:Prions / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D014404:Tubulin / Q000737:chemistry; D016875:tau Proteins / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D010455:Peptides; D011328:Prions; D014404:Tubulin; D016875:tau Proteins; D017239:Paclitaxel; D015739:Nocodazole
keywords: Aggregation; Anticancer Drug; Apoptosis; Cancer; Nanotechnology