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.
ABSTRACT
Retinoic acid (RA) agents possess anti-tumor activity through their ability to induce cellular differentiation. However, retinoids have not yet been translated into effective systemic treatments for most solid tumors. RA signaling is mediated by the following two nuclear retinoic receptor subtypes: the retinoic acid receptor (RAR) and the retinoic X receptor (RXR), and their isoforms. The identification of mutations in retinoid receptors and other RA signaling pathway genes in human cancers offers opportunities for target discovery, drug design, and personalized medicine for distinct molecular retinoid subtypes. For example, chromosomal translocation involving RARA occurs in acute promyelocytic leukemia (APL), and all-trans retinoic acid (ATRA) is a highly effective and even curative therapeutic for APL patients. Thus, retinoid-based target discovery presents an important line of attack toward designing new, more effective strategies for treating other cancer types. Here, we review retinoid signaling, provide an update on retinoid agents and the current clinical research on retinoids in cancer, and discuss how the retinoid pathway genotype affects the ability of retinoid agents to inhibit the growth of colorectal cancer (CRC) cells. We also deliberate on why retinoid agents have not shown clinical efficacy against solid tumors and discuss alternative strategies that could overcome the lack of efficacy.
