Abstract LB-4: Mechanisms by which the unfolded protein response/α-Basic-crystallin (CRYAB) regulates VEGF signaling of tumor endothelial cells

Abstract

Abstract Angiogenesis is an essential component of tumour development and is tightly regulated by a network of pro-angiogenic and anti-angiogenic factors. The tumour cells are known to produce many of the proteins that interact with vascular endothelial cells and drive the angiogenic process. Of the known angiogenic factors, VEGF has been established as a potent inducer of tumor angiogenesis. Like almost all secretory and membrane proteins, VEGF attains its final folded or assembly conformation in ER before making its way to its target organelles or the cell surface. The deleterious tumor microenvironment characterized by progressive hypoxia, nutrient starvation and acidosis results in the ER stress in the tumor vascular endothelial cells, which in turn leads to the unfolded/misfolded VEGF accumulated in the ER. Molecular chaperon proteins counteract the formation of aberrantly folded VEGF and allow its correct folding. One of molecular chaperons is CRYAB. It has been reported that CRYAB contains interactive sequences for VEGF. The misfolded VEGF interacts with BiP (chaperone immunoglobulin heavy chain-binding protein) causing its release from one or more of the three ER stress sensors [PKR-like ER kinase (PERK), inositol-requiring protein-1 (IRE1) and transcription factor 6 (ATF6)], which leads to activation of the unfolded protein response (UPR) pathway. All three sensor pathways can lead to chaperone induction but the IRE1 and ATF6 pathways are thought to play the major role in up-regulation of CRYAB. Activation of IRE1 generates a mature XBP-1 mRNA by unconventional splicing of XBP-1 pre-mRNA and activated XBP-1 up-regulates CRYAB. Activation of ATF6 results in its translocation to the Golgi apparatus and proteolytic cleavage to yield its cytosolic domain not only for directly up-regulating genes encoding CRYAB and folding catalysts, but also for assisting IRE1-dependent upregulation of CRYAB. An excessively elevated level of CRYAB has been detected in breast carcinomas, correlating with lymph node involvement resulting in metastasis and short term survival. Taken together, it is clear that CRYAB has the potential to a) protect VEGF from intracellular degradation thus maintaining the intracellular pool and b) increase VEGF secretion. Both these actions serve to enhance the autocrine VEGF signaling response which serves as one of strategies adapted by the tumor vasculature to perpetuate aberrant angiogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-4. doi:10.1158/1538-7445.AM2011-LB-4