Figure 8.

Proposed mechanism of glucocorticoid receptor (GR)–mitogen-inducible gene 6 (MIG6)-mediated epidermal growth factor receptor (EGFR) degradation and suppression by honokiol. (A) EGFR signaling plays a pivotal role in liver tumorigenesis by activating RAS/RAF/ERK and mechanistic (or mammalian) target of rapamycin complex 1 (mTORC1) signaling. FK506 binding protein 5 (FKBP5) and heat shock protein (HSP) cooperate to stabilize GR and inhibit its nuclear translocation in EGFR-expressing hepatocellular carcinoma cells. (B) Honokiol may cause GR to dissociate from the FKBP5/HSP complex. Once GR becomes free, it translocates to the nucleus and induces MIG6/ERRFI1 transcription to eventually cause the lysosomal degradation of EGFR. As a result, EGFR signaling and its downstream targets RAS/RAF/ERK and mTORC1 are suppressed.