NG25, a novel inhibitor of TAK1, suppresses KRAS -mutant colorectal cancer growth in vitro and in vivo

AbstractKRAS mutations are one of the most prevalent genetic alterations in colorectal cancer (CRC). Although directly targeting KRAS still is a challenge in anti-cancer therapies, alternatively inhibiting KRAS related signaling pathways has been approached effectively. Here we firstly reported that MAP kinase, transforming growth factor- β-activated kinase 1 (TAK1), commonly expressed in CRC cell lines and significantly associated withKRAS mutation status. Inhibition of TAK1 by the small molecular inhibitor NG25 could inhibit CRC cells proliferation in vitro and in vivo, especially inKRAS-mutant cells. NG25 induced caspase-dependent apoptosis inKRAS-mutant cells and in orthotopic CRC mouse models by regulating the B-cell lymphoma-2 (Bcl-2) family and the inhibitor of apoptosis protein (IAP) family. Besides inhibiting molecules downstream of MAPK, including ERK, JNK and p38 phosphorylation, NG25 could block NF- κB activation inKRAS-mutant cells. As a target gene of NF- κB, down-regulated XIAP expression may be not only involved in apoptosis induced by NG25, but also reducing the formation of TAK1-XIAP complex that can activate TAK1 downstream signaling pathways, which forms a positive feedback loop to further induce apoptosis inKRAS-mutant CRC cells. Together, these findings indicated that TAK1 is an important kinase for survival of CRCs harboringKRAS mutations, and that NG25 may be a potential therapeutic strategy forKRAS-mutant CRC.
Source: Apoptosis - Category: Molecular Biology Source Type: research