The hidden switches underlying ROR alpha-mediated circuits that critically regulate uncontrolled cell proliferation

Abstract

Prostaglandin E2 (PGE(2)) is known to have a key role in the development of colorectal cancer, but previous experiments showed its contrasting (i.e. tumor-promoting or tumor-suppressive) roles depending on experimental conditions. To elucidate the mechanisms underlying such contrasting roles of PGE(2) in tumorigenesis, we investigated all the previous experiments and found a new signal transduction pathway mediated by retinoic acid receptor-related orphan receptor (ROR)alpha, in which PGE(2)/PKC alpha-dependent phosphorylation of ROR alpha attenuates Wnt target gene expression in colon cancer cells. From mathematical simulations combined with biochemical experimentation, we revealed that ROR alpha induces a biphasic response of Wnt target genes to PGE(2) stimulation through a regulatory switch formed by an incoherent feedforward loop, which provides a mechanistic explanation on the contrasting roles of PGE(2) observed in previous experiments. More interestingly, we found that ROR alpha constitutes another regulatory switch formed by coupled positive and negative feedback loops, which regulates the hysteretic response of Wnt signaling and eventually converts a proliferative cellular state into an anti-proliferative state in a very delicate way. Our results indicate that ROR alpha is the key regulator at the center of these hidden switches that critically regulate cancer cell proliferation and thereby being a promising anti-cancer therapeutic target.