Effect of vitamin E δ-tocotrienol and aspirin on Wnt signaling in human colon cancer stem cells and in adenoma development in APCmin/+ mice.

Autor:	Husain K; Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Drive, Tampa, Florida 33612, United States., Coppola D; Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Drive, Tampa, Florida 33612, United States., Yang CS; Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, 160 Frelinghuysen Rd, Piscataway, NJ 08854, United States., Malafa MP; Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Drive, Tampa, Florida 33612, United States.
Jazyk:	angličtina
Zdroj:	Carcinogenesis [Carcinogenesis] 2024 Dec 30; Vol. 45 (12), pp. 881-892.
DOI:	10.1093/carcin/bgae041
Abstrakt:	In this study, we evaluated the effects of vitamin E δ-tocotrienol (DT3) and aspirin on Wnt signaling in human colon cancer stem cells (CCSCs) and in the prevention of adenoma formation in APCmin/+ mice. We found that knockdown of the adenomatous polyposis coli (APC) gene led to subsequent activation of Wnt signaling in colon epithelial cells (NCM460-APCsiRNA) and induction of β-catenin and its downstream target proteins c-MYC, cyclin D1, and survivin. When aspirin and DT3 were combined, cell growth and survival were inhibited and apoptosis was induced in colon epithelial cells and CCSCs. However, DT3 and/or aspirin had little or no effect on the control of normal colon epithelial cells (NCM460-NCsiRNA). The induction of apoptosis was directly related to the activation of caspase 8 and cleavage of BH3-interacting-domain (BID) to truncated BID. In addition, DT3- and/or aspirin-induced apoptosis was associated with cleaved Poly (ADP-ribose) polymerase (PARP), elevated levels of cytosolic cytochrome c and BAX, and depletion of antiapoptotic protein BCl-2 in CCSCs. The combination of aspirin and DT3 inhibited the self-renewal capacity, Wnt/β-catenin receptor activity, and expression of β-catenin and its downstream targets c-MYC, cyclin D1, and survivin in CCSCs. We also found that treatment with DT3 alone or combined with aspirin significantly inhibited intestinal adenoma formation and Wnt/β-catenin signaling and induced apoptosis, compared with vehicle, in APCmin/+ mice. Our study demonstrated a rationale for further investigation of the combination of DT3 and aspirin for colorectal cancer prevention and therapy. (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
Databáze:	MEDLINE
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