Journal
AUTOPHAGY
Volume 4, Issue 5, Pages 612-620Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/auto.5920
Keywords
apoptosis; autophagy; lymphocyte; lymphoma; dexamethasone; glucocorticoid; glucocorticosteroid; Bcl-2
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Funding
- NCI NIH HHS [R01 CA085804, CA85804, P30 CA43703-12, R01 CA042755, P30 CA043703, R01 CA42755] Funding Source: Medline
- NHLBI NIH HHS [T32 HL007147] Funding Source: Medline
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Glucocorticosteroid hormones, including prednisone and dexamethasone (Dex), have been used to treat lymphoid malignancies for many years because they readily induce apoptosis in immature lymphocytes lacking Bcl-2. However, elevated expression of the anti-apoptotic protein Bcl-2 inhibits apoptosis and contributes to glucocorticoid resistance. Using the Bcl-2-negative WEHI7.2 lymphoma line as an experimental model, we found that Dex not only induces apoptosis but also induces autophagy. The caspase inhibitor Z-VAD-fmk inhibited apoptosis but not autophagy in Dex-treated cells. Bcl-2 overexpression inhibited Dex-induced apoptosis even more potently than Z-VAD-fmk and, contrary to previous reports, Bcl-2 neither interacted with Beclin-1 nor inhibited autophagy. Rather, Bcl-2 overexpression facilitated detection of Dex-induced autophagy by both steady state methods and flux measurements, ostensibly due to apoptosis inhibition. Autophagy contributed to prolonged survival of Bcl-2-positive lymphoma cells following Dex treatment, as survival was reduced when autophagy was inhibited by 3-methyladenine. These findings emphasize the important interplay between apoptosis and autophagy and suggest a novel mechanism by which Bcl-2, which is frequently elevated in lymphoid malignancies, contributes to glucocorticoid resistance and survival of lymphoma cells.
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