Dr. Yu-Dong Zhou (Ole Miss) will present “Natural Products as Regulators of Oxygen Homeostasis” to the department.
Abstract: Transcription factor hypoxia-inducible factor-1 (HIF-1) dysregulation directly impacts cancer etiology and progression, while HIF-1 inhibition suppresses tumor growth and enhances the efficacy of radiation and chemotherapy. To discover novel HIF-1 inhibitors as potential drug leads for cancer, we took a natural product chemistry-based approach in combination with bioassays. A human breast tumor T47D cell-based reporter assay was established and validated. This assay was used to evaluate hundreds of purified natural products (small-molecule secondary metabolites), 15,000 natural product-rich marine invertebrate, and algae extracts, and 50,000 plant extracts from the U.S. National Cancer Institute’s Open Repository. Dozens of structurally novel and known compounds were isolated, identified, and their HIF-1 inhibitory activities characterized. These active compounds function through diverse pathways to inhibit HIF-1 activation, highlighting the potential of small-molecule HIF inhibitors as chemical probes for HIF biology and oxygen homeostasis. Employing mitochondrial complex I inhibitors as chemical probes, we uncovered that mitochondrial inhibitors trigger the endoplasmic reticulum (ER) stress response pathway to stall protein translation instead of through the more recognized AMPK pathway. This discovery revealed a new mechanism for mitochondrial inhibitors to regulate cellular signaling and paved the road for future research on the crosstalk between the ER and mitochondria. Meanwhile, a small scale screening campaign has led to the identification of natural product-based small-molecule HIF-1 activators. This research implicated that Golgi-mediated signaling pathway plays an important role in cellular oxygen homeostasis and HIF signaling.
Biography: After obtaining a Bachelor’s degree in Biochemistry at Fudan University (Shanghai, China), Dr. Yu-Dong Zhou moved to the US to pursue graduate education. She received her M.S. and Ph.D. degrees in Biochemistry and Molecular Biology at Emory University, Atlanta, Georgia, under the direction of Professor Kenneth E. Bernstein. Her subsequent postdoctoral research in the laboratory of Professor Steven L. McKnight at the University of Texas Southwestern Medical Center at Dallas (UTSW) led to the discovery and biological characterization of neuronal PAS domain protein 1 (NPAS1). Her natural product-focused research started after relocating to the University of Mississippi, first under the supervision of Dr. David S. Pasco and then as an independent scientist/research faculty (2000-present). Her UM research focuses on oxygen homeostasis, a fundamental principle of biology and medicine. Over the years, this UM molecular targeted anticancer natural product drug discovery effort has led to 40 research publications and two patents. Since joining Olemiss, Dr. Zhou has been a corresponding author or joint corresponding author on 33 original research publications. She has also served in the capacity of PI, co-PI, and investigator on a number of grants. Her research in natural product drug discovery, cancer biology, and cellular signaling has achieved significant recognition among her peers in the field, evidenced by invited presentations at national and international conferences, awards from the American Society of Pharmacognosy, and serving as a reviewer for high-impact scientific journals and funding agencies that include the NIH and Department of Defense.