Cytotoxicity of Recombinant Tamapin and Related Toxin-Like Peptides on Model Cell Lines
Por:
Ramírez-Cordero B., Toledano Y., Cano-Sánchez P., Hernández-López R., Flores-Solis D., Saucedo-Yáñez A.L., Chávez-Uribe I., Brieba L.G., Del Río-Portilla F.
Publicada:
1 jun 2014
Categoría:
Toxicology
Resumen:
The scorpion toxin tamapin displays the most potent and selective
blockage against KCa2.2 channels known to date. In this work, we report
the biosynthesis, three-dimensional structure, and cytotoxicity on
cancer cell lines (Jurkat E6-1 and human mammary breast cancer
MDA-MB-231) of recombinant tamapin and five related peptides bearing
mutations on residues (R6A,R7A, R13A, R6A-R7A, and GS-tamapin) that were
previously suggested to be important for tamapin's activity. The
indicated cell lines were used as they constitutively express KCa2.2
channels. The studied toxin-like peptides displayed lethal responses on
Jurkat T cells and breast cancer cells; their effect is dose- and
time-dependent with IC50 values in the nanomolar range. The order of
potency is r-tamapin > GS-tamapin > R6A > R13A > R6A-R7A > R7A for
Jurkat T cells and r-tamapin > R7A for MDA-MB-231 breast cancer cells.
Our structural determination by NMR demonstrated that r-tamapin
preserves the folding of the alpha KTx5 subfamily and that neither
single nor double alanine mutations affect the three-dimensional
structure of the wild-type peptide. In contrast, our activity assays
show that changes in cytotoxicity are related to the chemical nature of
certain residues. Our results suggest that the toxic activity of
r-tamapin on Jurkat and breast cancer cells could be mediated by the
interaction of charged residues in tamapin with KCa2.2 channels via the
apoptotic cell death pathway.
Filiaciones:
Ramírez-Cordero B.:
Univ Nacl Autonoma Mexico, Inst Quim, Mexico City 04510, DF, Mexico
Toledano Y.:
Univ Nacl Autonoma Mexico, Inst Ciencias Biomed, Mexico City 04510, DF, Mexico
Cano-Sánchez P.:
Univ Nacl Autonoma Mexico, Inst Quim, Mexico City 04510, DF, Mexico
Hernández-López R.:
Univ Nacl Autonoma Mexico, Inst Quim, Mexico City 04510, DF, Mexico
Flores-Solis D.:
Univ Nacl Autonoma Mexico, Inst Quim, Mexico City 04510, DF, Mexico
Saucedo-Yáñez A.L.:
Univ Nacl Autonoma Mexico, Inst Quim, Mexico City 04510, DF, Mexico
Chávez-Uribe I.:
Univ Nacl Autonoma Mexico, Inst Quim, Mexico City 04510, DF, Mexico
Brieba L.G.:
Laboratorio de Genómica Para la Biodiversidad, CINVESTAV Unidad Irapuato, Km. 9.6 Libramiento Norte Carr., Irapuato-León 36821, Irapuato Gto, Mexico
Del Río-Portilla F.:
Univ Nacl Autonoma Mexico, Inst Quim, Mexico City 04510, DF, Mexico
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