Dr. Ben C. B. Ko

Research Interests:
The molecular mechanism of cellular adaptations to stress; Natural product drug discovery and the chemical biology of anti-cancer compounds.

Our research focuses on the study of the molecular basis of cellular stress response. We use osmotic stress as our main experimental system. The exposure of mammalian cells to extracellular hypertonicity elicits a genetic program of adaptive cellular responses, including the induction of expression of aldose reductase, betaine transporter and Na +-dependent myoinositol transporter genes. Together these genes raise the intracellular level of organic osmolytes (sorbitol, betaine, and myoinositiol) which replaces intracellular electrolytes that are otherwise deleterious to normal cellular function. On the other hand, hypertonicity induces the expression of heat shock protein 70 (HSP-70) that acts as a molecular chaperone to protect cells from apoptotic cell death. We have previously identified and characterized the Osmotic Response Element- Binding Protein (OREBP), also known as TonEBP or NFAT5, a transcription factor that plays a pivotal role in mediating the hypertonic induction of these genes. Using biochemical, molecular and cellular approaches we study how OREBP is regulated in response to osmotic stress. In addition, through the use of transgenic mice we have revealed novel functions of OREBP in kidney water reabsorption and in lens cell growth. Interestingly, recent studies have implicated novel roles of OREBP in cell differentiation and migration. We are continuing our efforts to understand the regulation as well as the functions of OREBP at a molecular level.

The second area of our research is related to drug discovery from natural products, including Traditional Chinese Medicinal (TCM) herbs. Natural products have played pivotal roles in the drug discovery and development process. Over 50% of the approved cancer drugs are of natural origin. Since natural products may embody more “privileged structures” than purely synthetic chemical libraries, and they are a rich source of new chemical motifs. Our aim is to identify lead compounds that demonstrate significant anti-tumor activities in the experimental systems, with the goal of bringing them into pre-clinical drug development. On the other hand, through elucidating the molecular targets of these novel chemical entities using a chemical biology approach, we anticipate to reveal novel biochemical pathways that regulate cell growth or death. Our work has shown that pseudolaric acid B (PAB), a cytotoxic diterpenoid isolated from the tree bark of Pseudolarix kaempferi Gorden, has tubulin as its molecular target. We also showed that PAB circumvents P-glycoprotein overexpression-induced drug resistance and is effective in inhibiting tumor growth in vivo. Recently we have isolated and characterized several novel compounds that can induce autophagic cell death in cancer cells. At present we are further characterizing the compounds with respect to in vivo efficacy using a murine xenograft model and we are also studying the molecular basis of cytotoxic action of these compounds.