Mechanism of glucocorticoid action in lymphoid malignancy

Case Western Reserve University, Cleveland OH

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Abstract

The long-range goal of this research is to understand the mechanism of glucocorticosteroid action in lymphoid malignancy, providing information to guide development of novel therapeutic approaches. Glucocorticoids including prednisone and dexamethasone are among the most effective agents for treatment of lymphoid malignancies, but efficacy is limited by side effects and development of glucocorticoid resistance. Understanding the mechanism of glucocorticoid-induced apoptosis was the sole focus of this research until we recently discovered that glucocorticoids also induce autophagy. Remarkably glucocorticoids induce autophagy in lymphoma cells overexpressing the anti-apoptotic protein Bcl-2. Bcl-2 is elevated in the most common human lymphoid malignancies, including small lymphocytic lymphoma/chronic lymphocytic leukemia. Thus, our discovery that glucocorticoids induce autophagy in Bcl-2-positive lymphoma cells initiates an exciting new, clinically relevant, direction in our studies of glucocorticoid action in lymphoid malignancy. The goal is to understand fundamental mechanisms involved in induction of both apoptosis and autophagy by glucocorticoids. The Specific Aim is to investigate the role of key glucocorticoid-regulated genes, dig2/rtp801 and txnip, in the fundamental mechanism of glucocorticoid-induced apoptosis and autophagy, with the goal of identifying a common signaling pathway that leads to both of these processes.