Serina Cheung Biography: 
Serina Cheung is currently a second year MSc student in Dr. Marianne Koritzinsky’s lab. She is investigating the role of p38 mitogen-activation protein kinase in promoting the survival of castration-resistant prostate cancer under hypoxia. She will be presenting this work at the Keystone Symposia Tumor Metabolism conference in Banff, Alberta.
Abstract: Identifying mechanisms that determine sensitivity to p38 MAPK inhibition in castration-resistant prostate cancer
Androgen receptor (AR) signaling is the major driver of castration-resistant prostate cancer (CRPC). Tumor hypoxia increases AR signaling and is associated with treatment resistance. p38 MAP kinase is involved in AR signaling by activating heat shock protein 27, a chaperone for AR translocation. Additionally, the activation of p38 has been found to be an early response to hypoxia. However, the role of p38 in AR signaling under hypoxia in CRPC has not been explored. In this study, we evaluated the role of p38 on AR signaling under hypoxia in CRPC cells. Our results demonstrate that p38 activation is an early response to hypoxia. Hypoxia increased ligand-dependent AR binding to androgen-responsive element and expression of AR target genes. Pharmacological p38 inhibition decreased the hypoxia-induced increase in AR activity. Additionally, pharmacological inhibition and siRNA knockdown of p38 decreased cell proliferation and survival in prostate cancer cells dependent on AR signaling for survival. These results suggest further investigation of p38 inhibition as a therapeutic strategy to disrupt AR signaling in CPRC.
Ronald Wu Biography:
Ronald Wu is a PhD candidate in Dr. Brad Wouters lab at the University of Toronto and is investigating the role of hypoxia on oxygen-dependent DNA and histone demethylases in glioblastoma. Specifically, he is interested in the epigenetic mechanisms governing self-renewal and differentiation in this deadly brain tumour. This work will be presented at the AACR Annual Meeting 2020 in San Diego, California.
Abstract: Not given
Sandy Lee Biography:
Sandy Lee is a third year PhD student in Dr. Marianne Koritzinsky’s lab within the Institute of Medical Science at the University of Toronto. She is investigating how different levels of oxygen can mediate the folding process of a protein. She is interested in proteins that cause aggressive cancer phenotypes. Specifically, at AACR’s annual meeting in San Diego, California, she will be presenting how VEGF and CA9 folds under both normoxic and hypoxic conditions.
Stephanie Hulme Biography:
Stephanie Hulme is currently a second year MSc student in Dr. Marianne Koritzinsky’s lab. She is investigating protein secretion rates of VEGF and CA9 under normoxic and anoxic oxygen conditions. She will be presenting this project at the Keystone Symposia Tumour Metabolism conference in Banff, Alberta.
Sandy & Stephanie’s Abstract: Protein secretion rates of VEGF and CA9 in normoxia and hypoxia
Tumor hypoxia results in poor patient outcome due to treatment resistance as well as biological changes that stimulate angiogenesis, vasculogenesis, migration, invasion and immune suppression. These hypoxia-induced adverse biological changes are often mediated by membrane bound or secreted proteins through transcriptional and translational upregulation. Thus, understanding the regulation of how secreted proteins in hypoxia can therefore reveal novel therapeutic targets. Proteins that traverse through the secretory pathway form disulfide bonds in the endoplasmic reticulum (ER). Recent data from our lab have demonstrated that disulfide bond formation remains incomplete in ER cargo proteins like LDLR and Flu-HA in the absence of oxygen. To address whether hypoxia-induced proteins were likewise impaired, radioactive pulse chase assays were performed to measure disulfide bond formation and secretion capacity under both normoxic and hypoxic conditions. Here, we demonstrate that both hypoxia induced proteins carbonic anhydrase 9 (CA9) and vascular endothelial growth factor (VEGF) complete disulfide bond formation and are secreted with equal kinetics under hypoxia and normoxia. These proteins hence have a superior ability to be expressed in the absence of oxygen. Additionally, in a global in silico analysis of all proteins that traverse through the ER, we discovered that hypoxia-induced proteins on average contain fewer free cysteines and shorter-range disulfide bonds in comparison to other proteins. These traits may contribute to their superior ability to form correct disulfide bonds in hypoxia. These data show that the ability of proteins to form native disulfide bonds in hypoxia varies widely which can ultimately contribute to their expression in the extracellular space.
