Document Type
Article
Publication Date
1-7-2024
Abstract
APC mutation is the main driving mechanism of CRC development and leads to constitutively activated WNT signaling, overpopulation of ALDH+ stem cells (SCs), and incomplete differentiation. We previously reported that retinoic acid (RA) receptors are selectively expressed in ALDH+ SCs, which provides a way to target cancer SCs with retinoids to induce differentiation. Hypotheses: A functional link exists between the WNT and RA pathways, and APC mutation generates a WNT:RA imbalance that decreases retinoid-induced differentiation and increases ALDH+ SCs. Accordingly, to restore parity in WNT:RA signaling, we induce wt-APC expression in APC-mutant CRC cells, and we assess the ability of all-trans retinoic acid (ATRA) to induce differentiation. We found that ATRA increased expression of the WNT target gene, CYP26A1, and inducing wt-APC reduced this expression by 50%. Thus, the RA and WNT pathways crosstalk to modulate CYP26A1, which metabolizes retinoids. Moreover, inducing wt-APC augments ATRA-induced cell differentiation by: (i) decreasing cell proliferation; (ii) suppressing ALDH1A1 expression; (iii) decreasing ALDH+ SCs; and (iv) increasing neuroendocrine cell differentiation. A novel CYP26A1-based network that links WNT and RA signaling was also identified by NanoString profiling/bioinformatics analysis. Furthermore, CYP26A1 inhibitors sensitized CRC cells to the anti-proliferative effect of drugs that downregulate WNT signaling. Notably, in wt-APC-CRCs, decreased CYP26A1 improved patient survival. These findings have strong potential for clinical translation.
Recommended Citation
Facey, Caroline O.B.; Hunsu, Victoria O.; Zhang, Chi; Osmond, Brian; Opdenaker, Lynn M.; and Boman, Bruce M., "CYP26A1 Links WNT and Retinoic Acid Signaling: A Target to Differentiate ALDH+ Stem Cells in APC-Mutant CRC" (2024). Department of Pharmacology and Experimental Therapeutics Faculty Papers. Paper 154.
https://jdc.jefferson.edu/petfp/154
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Supplemental Materials
Language
English
Comments
This article is the author's final published version in Cancers, Volume 16, Issue 2, 2024, Article number 264.
The published version is available at https://doi.org/10.3390/cancers16020264. Copyright © 2024 by the authors. Licensee MDPI, Basel, Switzerland.