Canonical and non‐canonical pathway of unfolded protein response signaling (607.5)

Abstract

The endoplasmic reticulum (ER) is a principal site for folding and maturation of transmembrane, secretory and ER‐resident proteins. Perturbations that alter ER homeostasis can lead to accumulation of unfolded proteins, and a threat to all living cells. To cope with such stress, cells activate an intracellular signaling pathway ‐ the unfolded protein response (upr). It is an integrated intracellular signaling pathway that transmits information about the protein folding status in the ER lumen to the cytoplasm and the nucleus. If the protein‐folding defect is not corrected, cells undergo apoptosis. We have used Tunicamycin, a chemical mediator, a potent asparagine‐linked protein glycosylation inhibitor to induce upr and study the capillary endothelial cell fate, i.e., angiogenesis, a hallmark for tumor progression. Our results indicate ER stress developed due to protein denaturation, causes upr‐mediated cell cycle arrest in G1 and induction of apoptosis. Most importantly, Tunicamycin prevented double‐ and triple‐negative breast cancer progression ~55‐65%. To enhance the efficacy, we have examined nano‐formulated Tunicamycin. The results indicated gold anoparticles (20nm‐50nm) of Tunicamycin (1μg/ml) were three times more potent in inhibiting angiogenesis. There was upr‐mediated cell cycle arrest but no activation of apoptosis. This raised the possibility of a canonical and non‐canonical pathway.Grant Funding Source: Supported in part by grants from Susan G. Komen for the Cure BCTR0600582 (DKB) and NIH/NIMHD 2G12MD0