Apoptosis inhibition by Bcl-2 gives way to autophagy in glucocorticoid-treated lymphocytes.
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.
Swerdlow
Sarah
S
Department of Medicine, Comprehensive Cancer Center, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio 44106, USA.
McColl
Karen
K
Rong
Yiping
Y
Lam
Minh
M
Gupta
Anu
A
Distelhorst
Clark W
CW
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000473:pathology*; D051379:Mice; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D003907:Dexamethasone