| Abstrakt: |
Simple Summary: This manuscript reports the discovery of a mechanism that links two major cellular pathways, retinoic acid (RA) and WNT signaling, which are involved in colorectal cancer (CRC) development. The link between the two pathways is CYP26A1 enzyme, which controls intracellular RA metabolism and regulates RA signaling. Intracellular levels of CYP26A1 are regulated by WNT signaling, as CYP26A1 is a WNT target gene. Thus, the RA and WNT pathways crosstalk to modulate the metabolism of retinoids by CYP26A1. Mutation of the APC tumor suppressor gene drives CRC development by constitutively activating WNT signaling, which increases CYP26A1, its enzymatic degradation of retinoids, and decreases RA signaling. Consequently, when APC is mutant, reduced RA signaling leads to incomplete differentiation and overpopulation of ALDH+ stem cells. To restore retinoid-induced differentiation and reduce stem cell numbers, CYP26A1 levels will need to be lowered by inhibiting WNT signaling so that cells can respond to retinoids. Indeed, that is precisely what we observed in our study. 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. [ABSTRACT FROM AUTHOR] |
