Center for the Study of Biological Complexity

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Center for the Study of Biological Complexity L-citrulline coupled with Arsenic Trioxide as a potential inducer of the PERK/eIF2-alpha apoptotic pathway Peter Samuel BNFO 300

Center for the Study of Biological Complexity Cancer and Treatment Dysregulated cell proliferation 2nd leading cause of death in US, 3rd in the world Current cancer therapies fall short

Center for the Study of Biological Complexity Cellular Stress and Cell Death Cancer cells resist programmed cell death Cellular stress leads to programmed cell death or apoptosis (Appierto et al. 2009) How can one induce cellular stress? Adapted from https://images.novusbio.com/design/blog_image1.png & https://www.amplexhearing.com.au/wp-content/uploads/2016/04/Untitled-1.png

Center for the Study of Biological Complexity Reactive Oxygen Species (ROS)  Endoplasmic Reticulum Stress ? ROS  ER Stress (Verfaillie et al. 2012) Protein Endoplasmic Reticulum Kinase  phosphorylates eIF2-alpha Protein synthesis arrested Eventually, apoptosis Adapted from Velasco et al. (2010)

Center for the Study of Biological Complexity L-citrulline & Arsenic Trioxide (ATO)  ROS ATO induces apoptosis & an increase in ROS generation (Selvaraj et al. 2013) ATO is NO dependent (Kang et al. 2003) L-citrulline increases NO bioavailability (Wijnands et al. 2012)

Center for the Study of Biological Complexity My Experimental Question Do L-citrulline and ATO induce apoptosis mediated by PERK?

Center for the Study of Biological Complexity siRNA knock down of PERK GBM Cells No use of siRNA siRNA knock down of PERK Negative Control Treatment Group Sub-groups Saline L-citrulline ATO L-citrulline/ATO

Center for the Study of Biological Complexity siRNA How do siRNA ”knock down” the synthesis of proteins? Adapted from Wittrup et al. (2015)

Center for the Study of Biological Complexity Expected* Measurements – Western Blot Treatment Group Negative Control Group *These are not real Western Blots, simply predictions

Center for the Study of Biological Complexity Further Understanding Apoptosis Learning more about PERK/eIF2-alpha apoptotic pathway ROS  ER Stress  PERK  peIF2-alpha  apoptosis Different Results/Possible Explanation Different apoptotic pathway? Measure protein markers of other known apoptotic pathways Understanding the interactions between drug therapies and apoptosis in cancer

Center for the Study of Biological Complexity Questions?