NG25, a novel inhibitor of TAK1, suppresses KRAS-mutant colorectal cancer growth in vitro and in vivo
KRAS 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 with KRAS mutation status. Inhibition of TAK1 by the small molecular inhibitor NG25 could inhibit CRC cells proliferation in vitro and in vivo, especially in KRAS-mutant cells. NG25 induced caspase-dependent apoptosis in KRAS-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 in KRAS-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 in KRAS-mutant CRC cells. Together, these findings indicated that TAK1 is an important kinase for survival of CRCs harboring KRAS mutations, and that NG25 may be a potential therapeutic strategy for KRAS-mutant CRC.
KeywordsColorectal cancer KRAS NG25 TAK1 Bcl-2 XIAP
We thank Miss. Yue Zhang (Brown University) for language editing. This work was supported by research grants from the National Natural Science Foundation of China (Nos. 81471551 and 81630054).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no competing interests.
All animal experiments are in accordance with International Guidelines and Protocols and approved by the Institutional Animal Care and Use Committee at the Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences.
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