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SCI-26 Autophagy and Metabolism in Lymphoid Malignancies

Program: Scientific Program
Session: (Dys-) Regulation of Cell Metabolism in Lymphoid Neoplasia
Saturday, December 10, 2011, 4:00 PM-5:30 PM
Room 6A (San Diego Convention Center)

Clark W. Distelhorst, MD

Hematology & Oncology, Case Western Reserve University, Cleveland, OH

Cell stress, if left unchecked, leads to apoptosis and autophagy. Both are highly conserved, genetically encoded processes. Apoptosis is a programmed death mechanism, designed to eliminate cells that are defective or no longer needed as part of developmental programs. Autophagy, on the other hand, is a programmed survival mechanism designed to provide cells a temporary source of energy when nutritionally deficient. Since in autophagy (“self eating”) the cell generates energy at the expense of its own organelles, temporary survival leads to death if nutrition is not restored. Both apoptosis and autophagy are induced by glucocorticosteroid hormone (GH) treatment of lymphoid malignancies. Since the main effects of GH on lymphocytes are metabolic, it is likely that apoptosis and autophagy are responses to metabolic stress. Metabolic stress occurs because GH inhibits both glucose uptake and metabolism, as well as calcium signals required for optimal mitochondrial function. Gene expression profiling has provided insight into the complex pathways that mediate apoptosis and autophagy in GH-treated leukemia and lymphoma cells. Ultimately, the balance of pro-apoptotic and anti-apoptotic factors determines cell fate. Elevation of the pro-apoptotic protein Bim is a critical step in apoptosis induction by GH and is due to GH-mediated repression of a microRNA cluster (miR17-95) that normally represses Bim expression. In metabolically stressed cells, Bim elevation is counterbalanced by a proton-sensing G protein-coupled receptor, TDAG8, that signals an elevation of the anti-apoptotic protein Bcl-2, counterbalancing Bim elevation and inhibiting apoptosis. Gene expression profiling also provided insight into the mechanism of autophagy by detecting GH-mediated repression of the Src kinases Fyn and Lck and GH-mediated elevation of Dig2 (REDD1, RTP801). Fyn and Lck interact with the inositol 1,4,5-trisphosphate calcium channel and promote physiological calcium signals. By decreasing Fyn and Lck, GH inhibits calcium signals necessary for optimal mitochondrial metabolism, contributing to autophagy induction. Dig2 is a stress protein that inhibits mTOR signaling. The absence of the Dig2 stress response in Dig2 knockout mice significantly impairs autophagy induction, decreasing lymphocyte survival in GH-treated mice. In summary, both apoptosis and autophagy occur in lymphoid malignancies in response to metabolic stress, as illustrated by the effects of GH treatment. A goal for future studies is to tie these signaling components together into a logical signaling network and to target components of the signaling network for therapeutic purposes.

Disclosures: Distelhorst: Merck: Equity Ownership; Eli Lilly: Equity Ownership.