Nuclear GRP78 Promotes Metabolic Reprogramming and Therapeutic Resistance in Pancreatic Ductal Adenocarcinoma.

Protein complex of GRP78 and HIF-1a directly binds to HIF-1a own promoter and LDHA promoter, enhances the transcription of both HIF-1a and LDHA, while glucose deprivation increases GRP78 expression and further enhances HIF-1a and LDHA transcription. Therefore, crosstalk and integration of hypoxia- and hypoglycemia-responsive signaling critically impact PDA metabolic reprogramming and therapeutic resistance.