ReferenceID 2554
Preclinical investigation of ovatodiolide as a potential inhibitor of colon cancer stem cells via downregulating sphere-derived exosomal β-catenin/STAT3/miR-1246 cargoes
Am J Cancer Res
Patients with advanced-stage colon cancer often exhibit resistance against treatment and distant metastasis, both key contributors to poor prognosis. Emerging evidence indicates that cancer stem cells (CSCs), characteriz
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Record Fields
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- Reference Id
- 2554
- Evidence Id
- 19144
- Core Evidence Id
- 19144
- Source Reference Id
- 5114
- Herb2 Reference Id
- HBREF005911
- Subject Paper Key
- HBIN038417_32905416
- Pubmed Id
- 32905416
- Doi
- Paper Title
- Preclinical investigation of ovatodiolide as a potential inhibitor of colon cancer stem cells via downregulating sphere-derived exosomal β-catenin/STAT3/miR-1246 cargoes
- Paper Abstract
- Patients with advanced-stage colon cancer often exhibit resistance against treatment and distant metastasis, both key contributors to poor prognosis. Emerging evidence indicates that cancer stem cells (CSCs), characterized by the enhanced ability to self-renew, resist therapeutics, and promote metastasis, represents a clinical challenge to target. Alternative therapeutic approaches are urgently required. Here, we explored the feasibility of disrupting the intracellular communications between CSCs and the tumor microenvironment by way of exosomes. First, we demonstrated that exosomes secreted by colon tumorspheres (Exosp) promoted 5-FU resistance, migration, and tumorsphere formation. Exosp also increased the generation of cancer-associated fibroblasts and M2 polarized macrophages in vitro. Oncogenic molecules, including IL-6, p-STAT3, TGF-beta1, and beta-catenin, were identified as the cargoes of Exosp. Furthermore, the public database revealed the high abundance of miR-1246 in serum exosomes from colon cancer patients, and we verified in the Exosp from HCT116 and HT29 cells. Therapeutically, we demonstrated the ovatodiolide treatment reduced exosomal cargoes from tumorspheres (Exosp_OV). Exosp_OV were significantly less capable of promoting 5-FU resistance, migration, and tumorsphere formation when co-cultured with HCT116 and HT29 cells. Notably, Exosp_OV was less CAF- and M2 TAM-transformative. Computational docking analysis revealed that OV could bind and significantly reduced beta-catenin activity. Finally, mouse xenograft data indicated that ovatodiolide suppressed tumor growth via down-regulating IL-6, STAT3, beta-catenin expression, and serum exosomal miR-1246. In conclusion, our findings provided preclinical supports for ovatodiolide as a colon CSC inhibitor by reducing beta-catenin/STAT3/miR-1246 signaling conveyed by CSC derived exosomes.
- Journal
- Am J Cancer Res
- Publish Year
- 2020
- Experiment Subject
- mouse; patient; exosp; ht29 cells
- Experiment Type
- Animal & Cell Experiment
- Phenotype Related
- Tumor; Advanced-stage Colon Cancer; Colon Cancer; Cancer
- Paper Title Cn
- Paper Title En
- Preclinical investigation of ovatodiolide as a potential inhibitor of colon cancer stem cells via downregulating sphere-derived exosomal β-catenin/STAT3/miR-1246 cargoes
- Bilingual Status
- semi_complete