Cancer is second only to heart disease in causing death in the general American population and it is the major cause of non-accidental death in children. Lymphoma is the 5th ranked cancer problem. Lymphoma alone is estimated to cause the premature loss of over 250,000,000 person-years of life in the U.S. annually. Unlike localized solid tumors, hematological malignancies such as leukemia and lymphoma are naturally disseminated, making systemic treatment necessary. In addition, both cancers are especially notorious for developing resistance to therapy. Therefore, our long-term goals are to better understand lymphoma biology from multiple metabolic, molecular and signal transduction points of view so that ultimately, more comprehensive, less toxic and more successful treatment strategies can be developed. Virtually all tumors have altered bioenergetics and it is firmly established that PI-3K regulates bioenergetics in part, through mTOR and the mitochondrial Akt/hexokinase diad. In addition, we had previously demonstrated that B cell receptor- (BCR) mediated suppression of PI-3K/Akt drives B lymphoma death. Innovation: Using a new technology, the SeaHorse Extracellular Flux Analyzer, our present data show that BCR stimulation leads to differential modulation of lymphoma metabolism. This corresponds to dramatic changes in reactive oxygen species (ROS). Differential utilization of glycolytic or oxidative respiration were linked to specific phases of the cell cycle and to modulation of key signaling proteins in the BCR apoptotic response (e.g. c-Myc, Akt, CDK2 and p27Kip1). In addition, ROS appear to play important and distinct roles in lymphoma signal transduction since we find that thiol antioxidants deactivate Akt and CDK2. Importantly, B cell receptor (BCR) cross-linking, modulation of Akt and manipulation of cellular respiration, all resulted in the rapid loss of Cu/Zn superoxide dismutase (SOD1) protein expression and not MnSOD (SOD2) or catalase, showing that SOD1 is a critical target of BCR signaling. The loss of SOD1 precisely correlated with downstream BCR signaling events that lead to ROS induction, cell cycle changes, growth arrest and apoptosis, including: modulation of c-Myc and p27Kip1 and dephosphorylation of Akt. Hence, together, these data provide strong evidence that ROS derived from enzymatic systems and metabolic output are tightly coupled to the management of signal protein activity and to cell cycle progression. SOD1 seems to be a central integrator of these processes. Impact: A better understanding of these basic biochemical processes in lymphoma will ultimately help us to design more comprehensive strategies that exploit RedOx biology, the cell cycle and a universal tumor anomaly such as altered metabolism, to obtain better cancer treatment outcomes.
Our specific aims are to: 1), examine the inter-relationships of metabolically and enzymatically-derived ROS on SOD1 expression and signal protein activation and 2), to determine the underlying mechanism regulating BCR-modulated SOD1 expression.
In the United States, there are over 1,000,000 new cancer cases and more than 500,000 cancer-related deaths annually. We have found close cooperation between reactive oxygen species induction, metabolism, expression of the antioxidant enzyme, SOD1, regulation of bioenergetics, activation of Akt and cell cycle progression in lymphoma. A better understanding of these basic biochemical processes first in lymphoma will help us to design more comprehensive treatment strategies that exploit ROS and RedOx biology, the cell cycle and a fundamental process like cellular metabolism, to obtain better cancer treatment outcomes.