Honokiol Affects Stem Cell Viability by Suppressing Oncogenic YAP1 Function to Inhibit Colon Tumorigenesis.
Honokiol (HNK) is a biphenolic compound that has been used in traditional medicine for treating various ailments, including cancers. In this study, we determined the effect of HNK on colon cancer cells in culture and in a colitis-associated cancer model. HNK treatment inhibited proliferation and colony formation while inducing apoptosis. In addition, HNK suppressed colonosphere formation. Molecular docking suggests that HNK interacts with reserve stem cell marker protein DCLK1, with a binding energy of -7.0 Kcal/mol. In vitro kinase assays demonstrated that HNK suppressed the DCLK1 kinase activity. HNK also suppressed the expression of additional cancer stem cell marker proteins LGR5 and CD44. The Hippo signaling pathway is active in intestinal stem cells. In the canonical pathway, YAP1 is phosphorylated at Ser127 by upstream Mst1/2 and Lats1/2. This results in the sequestration of YAP1 in the cytoplasm, thereby not allowing YAP1 to translocate to the nucleus and interact with TEAD1-4 transcription factors to induce gene expression. However, HNK suppressed Ser127 phosphorylation in YAP1, but the protein remains sequestered in the cytoplasm. We further determined that this occurs by YAP1 interacting with PUMA. To determine if this also occurs in vivo, we performed studies in an AOM/DSS induced colitis-associated cancer model. HNK administered by oral gavage at a dose of 5mg/kg bw for 24 weeks demonstrated a significant reduction in the expression of YAP1 and TEAD1 and in the stem marker proteins. Together, these data suggest that HNK prevents colon tumorigenesis in part by inducing PUMA-YAP1 interaction and cytoplasmic sequestration, thereby suppressing the oncogenic YAP1 activity.
['Subramaniam|Dharmalingam|D|0000-0002-2710-485X', 'Ponnurangam|Sivapriya|S|', 'Ramalingam|Satish|S|', 'Kwatra|Deep|D|', 'Dandawate|Prasad|P|', 'Weir|Scott J|SJ|0000-0002-8020-434X', 'Umar|Shahid|S|', 'Jensen|Roy A|RA|0000-0003-4430-2281', 'Anant|Shrikant|S|0000-0003-4193-3053']
D048868:Adaptor Proteins, Signal Transducing D000818:Animals D017209:Apoptosis D051017:Apoptosis Regulatory Proteins D014408:Biomarkers, Tumor D001713:Biphenyl Compounds D063646:Carcinogenesis D045744:Cell Line, Tumor D049109:Cell Proliferation D002470:Cell Survival D003092:Colitis D003110:Colonic Neoplasms D000089742:Doublecortin-Like Kinases D015536:Down-Regulation D000090683:Hippo Signaling Pathway D006801:Humans D047908:Intracellular Signaling Peptides and Proteins D017705:Lignans D008297:Male D008813:Mice, Inbred ICR D008954:Models, Biological D014411:Neoplastic Stem Cells D011485:Protein Binding D017346:Protein Serine-Threonine Kinases D011518:Proto-Oncogene Proteins D015398:Signal Transduction D014157:Transcription Factors D014410:Tumor Stem Cell Assay D000091102:YAP-Signaling Proteins
apoptosis colonospheres cancer stem cells hippo signaling colitis associated cancer doublecortin-like kinase 1 leucine-rich repeat-containing G-protein coupled receptor 5 spheroids