Hypoxia endoplasmic reticulum stress and chemoresistance: dangerous liaisons

摘要

Hypoxia and ER stress select aggressive tumor clones. Hypoxia increases the stabilization of the hypoxia-inducible factor-1α (HIF-1α), by preventing its degradation operated by prolyl hydroxylase dioxygenase (PHDs) enzymes. Together with chemotherapy and nutrient shortage, hypoxia is also a strong inducer of ER stress. The increased burden of unfolded proteins is sensed by the glucose-regulated protein 78 (GRP78), which is also a HIF-1α-target gene. The GRP78 downstream effectors – namely inositol-requiring enzyme-1α (IRE1α), activating transcription factor-6 (ATF6) and protein kinase R-like endoplasmic reticulum kinase (PERK) – are activated. IRE1α induces the splicing (s) of X-box-binding protein 1 (XBP-1) into its active form; PERK phosphorylates the eukariotic initiating factor 2α (eIF2α) that increases the translation of activating transcription factor-4 (ATF4); ATF6 is cleaved by the Golgi site-1/site-2 proteases (S1P, S2P) into its nuclear (N) translocated form. XBP-1 s, ATF4 and ATF6N cooperate with HIF-1α in increasing the transcription of genes involved in neo-angiogenesis (vascular endothelial growth factor, VEGF), invasion (matrix metalloproteases, MMP), metabolic rewiring (glucose transporter 1, GLUT1), pH homeostasis (carbonic anhydrases, CAs), drug efflux (multidrug resistance 1, MDR1). These coordinated transcriptional programs promote the selection of tumor clones adapted to survive in unfavorable conditions, characterized by chemoresistant and pro-metastatic phenotypes