RT Journal Article
SR Electronic
T1 A New Mechanism of 6-((2-(Dimethylamino)ethyl)amino)-3-hydroxy-7<em>H</em>-indeno(2,1-<em>c</em>)quinolin-7-one Dihydrochloride (TAS-103) Action Discovered by Target Screening with Drug-Immobilized Affinity Beads
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 987
OP 994
DO 10.1124/mol.107.043307
VO 73
IS 3
A1 Yoshida, Makoto
A1 Kabe, Yasuaki
A1 Wada, Tadashi
A1 Asai, Akira
A1 Handa, Hiroshi
YR 2008
UL http://molpharm.aspetjournals.org/content/73/3/987.abstract
AB 6-((2-(Dimethylamino)ethyl)amino)-3-hydroxy-7H-indeno(2,1-c)-quinolin-7-one dihydrochloride (TAS-103) is a quinoline derivative that displays antitumor activity in murine and human tumor models. TAS-103 has been reported to be a potent topoisomerase II poison. However, other studies have indicated that cellular susceptibility to TAS-103 is not correlated with topoisomerase II expression. Because the direct target of TAS-103 remained unclear, we searched for a TAS-103 binding protein using high-performance affinity latex beads. We obtained a component of the signal recognition particle (SRP) as a TAS-103 binding protein. This component is a 54-kDa subunit (SRP54) of SRP, which mediates the proper delivery of secretory proteins in cells. We fractioned 293T cell lysates using gel-filtration chromatography and performed a coimmunoprecipitation assay using 293T cells expressing FLAG-tagged SRP54. The results revealed that TAS-103 disrupts SRP complex formation and reduces the amount of SRP14 and SRP19. TAS-103 treatment and RNAi-mediated knockdown of SRP54 or SRP14 promoted accumulation of the exogenously expressed chimeric protein interleukin-6-FLAG inside cells. In conclusion, we identified signal recognition particle as a target of TAS-103 by using affinity latex beads. This provides new insights into the mechanism underlying the effects of chemotherapies comprising TAS-103 and demonstrates the usefulness of the affinity beads. The American Society for Pharmacology and Experimental Therapeutics