Fig. 3
From: Hypoxia, endoplasmic reticulum stress and chemoresistance: dangerous liaisons
Hypoxia and UPR cooperate in inducing chemoresistance. In hypoxic cells, the ER stress sensors are activated and cooperate in inducing chemoresistance. glucose-regulated protein 78 (GRP78) increases the anti-apoptotic Bcl-2/Bax ratio and transcriptionally induces ABC transporter B1/multidrug resistance 1 (ABCB1/MDR1) gene by activating Janus kinase (JNK). Protein kinase R-like endoplasmic reticulum kinase/eukariotic initiating factor 2α/activating transcription factor-4 (PERK/eIF2α/ATF-4) axis stabilizes the anti-apoptotic factor forkhead box O-1 (FOXO-1) and activates the transcription factor erythroid-derived 2-like 2 (Nrf2), which in turn up-regulates ABC transporter C1/multidrug resistance related protein 1 (ABCC1/MRP1), antioxidant enzymes and matrix metalloprotease 9 (MMP9). Together with PERK-dependent signalling, also inositol-requiring enzyme-1α/X-box-binding protein 1 (IRE1α/XBP-1) and activating transcription factor-6 (ATF6)-dependent axes support hypoxia-inducible factor-1α (HIF-1α) transcriptional program, contributing to the chemoresistance typical of hypoxic tumors