Novel small-molecule compounds that affect cellular morphogenesis in yeast and mammalian cells.
Drugs affecting cellular morphological changes leading to tumor cell migration and invasion are desirable for cancer therapy. In the present study, we screened for small-molecule compounds that affect the cellular morphology of both unicellular yeast and mammalian HEK293 cells to identify drug candidates. The yeast formin protein Bni1 and Src homology 3 (SH3)-pleckstrin homology (PH) domain protein Boi1, which are required for proper morphogenesis, cause growth defects when overexpressed in yeast. Using this system, we screened a chemical library consisting of ～8000 compounds to identify drug candidates that suppress these growth defects. None of the screened compounds induced morphological changes in vegetatively growing yeast cells, but several compounds had inhibitory effects on pheromone-induced projection formation and actin localization, suggesting that these compounds affected a specific stage of morphogenesis. Five of the compounds also induced morphological changes in mammalian HEK293 cells. Among the identified compounds, BTB03156, 2-[(4-chlorophenyl)sulfonyl]-1-methyl-3,5-dinitrobenzene, and BTB02467, 1-[(4-chlorophenyl)sulfonyl]-2-nitro-4-(trifluoromethyl)benzene, although they have similar structures, displayed differing effects on the yeast growth defects caused by latrunculin A, an actin polymerization inhibitor. The chemical library compounds identified using this in vivo screening approach are simple, cell-permeable molecules, and therefore may be useful in the development of therapeutic drugs for cancer metastasis and other actin-related diseases.
Department of Applied Molecular Bioscience, Yamaguchi University Graduate School of Medicine.
Tomoaki
T
Fukunaga
Mikiko
M
Nakamura
Takao
T
Kitagawa
Ramida
R
Watanapokasin
Hisashi
H
Hoshida
Rinji
R
Akada
D000199:Actins / Q000737:chemistry / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008840:Microfilament Proteins / Q000737:chemistry / Q000378:metabolism*; D009024:Morphogenesis / Q000187:drug effects; D012441:Saccharomyces cerevisiae; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D054852:Small Molecule Libraries / Q000494:pharmacology*
D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; C099888:BOI1 protein, S cerevisiae; C105191:Bni1 protein, S cerevisiae; D008840:Microfilament Proteins; D029701:Saccharomyces cerevisiae Proteins; D054852:Small Molecule Libraries