title: LYTAK1, a novel TAK1 inhibitor, suppresses KRAS mutant colorectal cancer cell growth in vitro and in vivo.
abstract: KRAS mutation in colorectal cancer (CRC) activates transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) to promote tumor progression. In the current study, we explored the potential effect of LYTAK1, a novel TAK1 inhibitor, against KRAS mutant CRC cells in vitro and in vivo. We found that LYTAK1 dose-dependently inhibited KRAS mutant CRC cell (HT-29 and SW-620 lines) growth, and induced cell cycle G1-S arrest. Further, LYTAK1 activated apoptosis in HT-29 cells and SW-620 cells, and apoptosis inhibitors almost reversed LYTAK1-mediated growth inhibition. While in KRAS wild-type (WT) CRC cell lines (DLD-1 and HCT-116), LYTAK1 had almost no effect on cell growth, cell cycle progression, or cell apoptosis. In KRAS mutant HT-29 cells and SW-260 cells, LYTAK1 blocked TAK1 activation or phosphorylation at Thr-184/187. Activation of nuclear factor κB (NF-κB) in these cells, detected by phosphorylations of p65 and IκB kinase α (IKKα) as well as expression of NF-κB-regulated gene cyclin D1, was significantly inhibited by LYTAK1. Further, LYTAK1 treatment resulted in downregulation of β-catenin and Wnt response gene Axin 2, indicating Wnt inactivation. In vivo, oral LYTAK1 significantly inhibited HT-29 xenograft growth in nude mice. Together, these results show that LYTAK1 inhibits KRAS mutant CRC cell growth both in vitro and in vivo. LYTAK1 might be investigated as a novel agent against CRC with KRAS mutation.
authors.affiliation: The Core Laboratory of the Suzhou Cancer Center and Department of Radiotherapy, Suzhou Hospital Affiliated to Nanjing Medical University, Suzhou, China.
authors.forename: Jundong
authors.initials: J
authors.lastname: Zhou
authors.forename: Bing
authors.initials: B
authors.lastname: Zheng
authors.forename: Jiansong
authors.initials: J
authors.lastname: Ji
authors.forename: Fei
authors.initials: F
authors.lastname: Shen
authors.forename: Han
authors.initials: H
authors.lastname: Min
authors.forename: Biao
authors.initials: B
authors.lastname: Liu
authors.forename: Jinchang
authors.initials: J
authors.lastname: Wu
authors.forename: Shuyu
authors.initials: S
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005260:Female; D019073:HT29 Cells; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D000970:Antineoplastic Agents; D020930:MAP Kinase Kinase Kinases; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000099151:MAP Kinase Kinase Kinase 7; C117307:KRAS protein, human