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

Dongkwan Shin, Ik Soo Kim, Ji Min Lee, Sung-Young Shin, Jong Hoon Lee, Sung Hee Baek, Kwang Hyun Cho

Research output: Contribution to journalArticleResearchpeer-review

20 Citations (Scopus)

Abstract

Prostaglandin E2 (PGE2) 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 PGE2 in tumorigenesis, we investigated all the previous experiments and found a new signal transduction pathway mediated by retinoic acid receptor-related orphan receptor (ROR)α, in which PGE 2/PKCα-dependent phosphorylation of RORα attenuates Wnt target gene expression in colon cancer cells. From mathematical simulations combined with biochemical experimentation, we revealed that RORα induces a biphasic response of Wnt target genes to PGE2 stimulation through a regulatory switch formed by an incoherent feedforward loop, which provides a mechanistic explanation on the contrasting roles of PGE2 observed in previous experiments. More interestingly, we found that RORα 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 RORα 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.

Original languageEnglish
Pages (from-to)338-348
Number of pages11
JournalJournal of Molecular Cell Biology
Volume6
Issue number4
DOIs
Publication statusPublished - 1 Aug 2014
Externally publishedYes

Keywords

  • biphasic response
  • colorectal cancer
  • hysteresis
  • mathematical modeling
  • RORα
  • systems biology
  • Wnt signaling

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