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Autophagy in siRNA-mediated PRKAR1A knockdown canine osteosarcoma cells

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Title: Autophagy in siRNA-mediated PRKAR1A knockdown canine osteosarcoma cells
Author: Wong, Jeremy
Department: Department of Pathobiology
Program: Pathobiology
Advisor: Wood, Geoffrey A.
Abstract: Canine Osteosarcoma (OSA) is a highly malignant form of bone cancer with a mean survival time of only one year even with aggressive treatment. The poor prognosis of OSA could be due to the ability of OSA cells to resist chemotherapy-induced cell death by entering autophagy. Autophagy, or “self-eating”, is an evolutionarily conserved intracellular catabolic process which plays an important role in adaptation to environmental changes and maintenance of cellular homeostasis. Cancer cells have been shown to enter autophagy and become resistant to chemotherapy; however, the role of autophagy in OSA is currently unknown. Human and canine OSA have numerous similarities including variation in the expression of a gene called PRKAR1A. Patients with low PRKAR1A-expressing OSA have longer post-chemotherapy survival times than high PRKAR1A-expressing OSA in both species. As PRKAR1A interacts with multiple upstream regulators of mammalian target of rapamycin (mTOR), low-PRKAR1A expressing OSA could potentially reduce the autophagic response through mTOR and lead to better chemo-sensitivity. siRNA-mediated PRKAR1A knockdown of canine OSA cells showed a decrease in autophagic response when compared to control cells. However, clonogenic survival assays of treatments showed no statistically significant differences across all treatments. The cytoprotective effects of autophagy could likely be driven by elements more than just the down-regulation of PRKAR1A alone. Future studies are needed to decipher the relationship between autophagy and chemo-resistance of OSA.
Date: 2016-08
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