Mammalian mitotic centromere-associated kinesin (MCAK): a new molecular target of sulfoquinovosylacylglycerols novel antitumor and immunosuppressive agents

• Published in: The FEBS journal 2005-05, Vol.272 (9), p.2132-2140
• Main Authors: Aoki, Satoko, Ohta, Keisuke, Yamazaki, Takayuki, Sugawara, Fumio, Sakaguchi, Kengo
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Cell division; CHO Cells; Cricetinae; Deoxyribonucleic acid; DNA; DNA-Directed DNA Polymerase - metabolism; Drosophila melanogaster; Glycolipids - chemistry; Glycolipids - metabolism; Glycolipids - pharmacology; Humans; Immune system; Immunosuppressive Agents - chemistry; Immunosuppressive Agents - metabolism; Immunosuppressive Agents - pharmacology; Kinesin - genetics; Kinesin - metabolism; Mammals; Microtubules - metabolism; Molecular biology; Molecular Sequence Data; Molecular Structure; Peptide Library; Protein Binding; Surface Plasmon Resonance; Tumors
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/j.1742-4658.2005.04600.x

Sulfoquinovosylacylglycerols (SQAGs), in particular compounds with C18 fatty acid(s) on the glycerol moiety, may be clinically promising antitumor and/or immunosuppressive agents. They were found originally as inhibitors of mammalian DNA polymerases. However, SQAGs can arrest cultured mammalian cells not only at S phase but also at M phase, suggesting they have several molecular targets. A screen for candidate target molecules using a T7 phage display method identified an amino acid sequence. An homology search showed this to be a mammalian mitotic centromere-associated kinesin (MCAK), rather than a DNA polymerase. Analyses showed SQAGs bound to recombinant MCAK with a K(D)=3.1x10(-4) to 6.2x10-5 M. An in vivo microtubule depolymerization assay, using EGFP-full length MCAK fusion constructs, indicated inhibition of the microtubule depolymerization activity of MCAK. From these results, we conclude that clinically promising SQAGs have at least two different molecular targets, DNA polymerases and MCAK. It should be stressed that inhibitors of MCAK have never been reported previously so that there is a major potential for clinical utility.