The Ginsenoside Compound K Suppresses Stem-Cell-like Properties and Colorectal Cancer Metastasis by Targeting Hypoxia-Driven Nur77-Akt Feed-Forward Signaling

Hypoxia reprograms cancer stem cells. Nur77, an orphan nuclear receptor, highly expresses and facilitates colorectal cancer (CRC) stemness and metastasis under a hypoxic microenvironment. However, safe and effective small molecules that target Nur77 for CSC depletion remain unexplored. Here, we report our identification of the ginsenoside compound K (CK) as a new ligand of Nur77. CK strongly inhibits hypoxia-induced CRC sphere formation and CSC phenotypes in a Nur77-dependent manner. Hypoxia induces an intriguing Nur77-Akt feed-forward loop, resulting in reinforced PI3K/Akt signaling that is druggable by targeting Nur77. CK directly binds and modulates Nur77 phosphorylation to block the Nur77-Akt activation loop by disassociating Nur77 from the p63-bound Dicer promoter. The transcription of Dicer that is silenced under a hypoxia microenvironment is thus reactivated by CK. Consequently, the expression and processing capability of microRNA let-7i-5p are significantly increased, which targets PIK3CA mRNA for decay. The in vivo results showed that CK suppresses cancer stemness and metastasis without causing significant adverse effects. Given that the majority of FDA-approved and currently clinically tested PI3K/Akt inhibitors are reversible ATP-competitive kinase antagonists, targeting Nur77 for PI3K/Akt inactivation may provide an alternative strategy to overcoming concerns about drug selectivity and safety. The mechanistic target identification provides a basis for exploring CK as a promising nutraceutical against CRC.