APOPTOSIS IN BURKITT-LYMPHOMA CELLS IS PREVENTED BY PROMOTION OF CYSTEINE UPTAKE

Burkitt lymphoma (BL) cells ave highly sensitive to sub-optimal growth conditions and undergo apoptosis when seeded at reduced serum concent ration or low cell density. Irradiated fibroblasts can protect BL cell s from apoptosis induced by lowering the serum concentration or cell d ensity through secretion of a survival- and proliferation-promoting ac tivity which is soluble and labile. Murine B cells have a restricted u ptake capacity for cystine and require cysteine for proliferation, whi ch can be supplied efficiently by feeder cells. Therefore, we have stu died the role of cysteine and other compounds with free thiol groups f or survival and proliferation of BL cells. Cysteine, when added alone, exerted strong toxicity on BL cells. This toxicity could be counterac ted by the addition of catalase, pyruvate or bathocuproine disulfonate (BCS), all of which interfere with the production of hydrogen peroxid e. Inhibition of the toxicity of cysteine was necessary to unravel the survival-and growth-promoting activity of cysteine at low cell densit y. alpha-Thioglycerol, beta-mercaptoethanol and dithiothreitol had sim ilar toxic activity in the absence of catalase, pyruvate and BCS and, through stimulation of cysteine uptake and glutathione synthesis, disp layed a similar survival- and growth-promoting activity in the presenc e of the protective agents. The survival- and proliferation-inducing a ctivity of thiol compounds in the presence of catalase, pyruvate and B CS was not associated with induction of BCL-2 or BAX. Cysteine/cystine uptake and the intra/cellular glutathione level are thus important pa rameters, determining the susceptibility vs. resistance of BL cells to apoptosis. (C) 1998 Wiley-Liss, Inc.