Apoptosis to autophagy switch triggered by the MHC class III-encoded receptor for advanced glycation endproducts (RAGE).

The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin gene superfamily, encoded within the major histocompatability complex class III region. Its multiple ligands include the high mobility group box 1 chromatin binding protein, HMGB1. Recently we reported that RAGE-HMGB1 critically regulates autophagy and apoptosis in pancreatic cancer cells in vivo and in vitro in response to chemotherapy. RAGE inhibits apoptosis ("programmed cell death") by a p53 transcription-independent pathway during the response to chemotherapeutic agents. RAGE sustains autophagy ("programmed cell survival") associated with decreased phosphorylation of the mammalian target of rapamycin (mTOR) and increased Beclin 1-Vps34 interaction. These findings provide insight into how autophagy- and apoptosis-crossregulatory molecules interact in response to cellular stress including tumor therapy.