Abstract B68: Screening for the compound that induces cell death selectively in β-catenin mutant tumor cells

The Wnt signal transduction pathway plays a central role for the cell proliferation, differentiation and apoptosis. β-catenin, a component of Wnt pathway, translocates to nucleus and forms an active complex with TCF4, leading to activate cell growth signaling, and this activity is tightly regulated by the “destruction complex” consisting of Axin, APC, GSK3β and CK1α. However, when β-catenin is actively mutated, this cell growth signaling would be hyperactive and drive oncogenesis. As β-catenin is mutated in up to 10% of all sporadic colon carcinomas resulting from point mutations or in-frame deletions of serine and threonine residues phosphorylated by GSK3β, mutated β-catenin has been considered as promising targets for therapeutic intervention.

Therefore, we screened the compound that induced cell death selectively in tumor cell lines harboring β-catenin mutation from an in-house natural product library, and finally we isolated and found that nonactin, a well-known antibiotics, exhibited this activity. To confirm its apoptosis-inducing ability selectivity in β-catenin mutated cell lines, we examined the effect of nonactin on cell viability in 15 human tumor cell lines. Nonactin potently induced PARP-cleavage in 5 cell lines harboring β-catenin mutation (A427, HCT116, LS-174T, SK-MEL-1, SW48 cells), whereas the others, which do not harbor a mutation of β-catenin activation, were resistant to nonactin. In addition, overexpression of actively mutated β-catenin accelerated apoptosis induced by nonactin in the nonactin-resistant A375 cells, and β-catenin knockdown by siRNA reduced nonactin-induced apoptosis in HCT116 cells. Furthermore, nonactin induced tumor regression only in β-catenin mutated HCT116 xenograft mice.

Taken together, these findings suggested that the β-catenin mutated tumor cell lines are highly sensitive to nonactin, and it would be potential drug-seed for tumor cells harboring β-catenin mutation.

Citation Format: Yuki Shikata, Masaki Kiga, Etsu Tashiro, Masaya Imoto. Screening for the compound that induces cell death selectively in β-catenin mutant tumor cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B68.