Abstract
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.
Highlights
Colon cancer is a second leading cause of adult cancer related death in the UnitedStates and is associated with a high mortality rate [1]
We previously demonstrated that HNK in combination with radiation targets notch signaling to inhibit colon cancer and melanoma stem cells [7]
We have demonstrated that doublecortin calmodulin-like kinase 1 (DCLK1) marks the +4 tuft cells serves as a reserve stem cell marker when LGR5+ cells are removed as a result of injury [15,16]
Summary
Colon cancer is a second leading cause of adult cancer related death in the UnitedStates and is associated with a high mortality rate [1]. Colon cancer is a second leading cause of adult cancer related death in the United. Patients with inflammatory bowel disease (IBD) are at increased risk of developing colorectal cancer. An association between inflammatory bowel disease and the development of colitis-associated cancer (CAC) has been reported [2]. The American Cancer Society estimates that in 2021, 101,270 new cases (52,590 men and 51,680 women) would be diagnosed with colon cancer, and of these 52,980 would result in death (28,520 men and 24,460 women) [1]. While current chemotherapy, including a combination of 5-flurouracil, oxaliplatin, and irinotecan coupled with surgical and radiation therapy, shows an initial response, it is often inadequate and results in severe side effects. Novel targeted agents and combinations have been identified, these have not been very effective or curative in patients with advanced cancer
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