Apoptosis inhibition by Bcl-2 gives way to autophagy in glucocorticoid-treated lymphocytes
Apoptosis inhibition by Bcl-2 gives way to autophagy in glucocorticoid-treated lymphocytes
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DOI：
10.4161/auto.5920
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发表时间：
2008-07
期刊：
影响因子：
13.3
通讯作者：
Sarah J. Swerdlow;Karen S McColl;Y. Rong;M. Lam;Anu Gupta;C. Distelhorst
中科院分区：
文献类型：
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作者：
Sarah J. Swerdlow;Karen S McColl;Y. Rong;M. Lam;Anu Gupta;C. Distelhorst
糖皮质激素，包括泼尼松和地塞米松（Dex），已被用于治疗淋巴恶性肿瘤多年，因为它们容易诱导缺乏Bcl-2的未成熟淋巴细胞凋亡。然而，抗凋亡蛋白Bcl-2的表达升高抑制细胞凋亡，并有助于糖皮质激素抵抗。以Bcl-2阴性的WEHI7.2淋巴瘤细胞系为实验模型，我们发现Dex不仅诱导细胞凋亡，而且诱导自噬。半胱天冬酶抑制剂Z-VAD-favorite抑制细胞凋亡，但不自噬在右旋糖酐处理的细胞。Bcl-2过表达抑制Dex诱导的细胞凋亡，甚至比Z-VAD-fastin更有效，与以前的报道相反，Bcl-2既不与Beclin-1相互作用，也不抑制自噬。相反，Bcl-2过表达促进检测Dex诱导的自噬的稳态方法和流量测量，表面上是由于细胞凋亡抑制。自噬有助于延长Dex治疗后Bcl-2阳性淋巴瘤细胞的存活时间，因为当自噬被3-甲基腺嘌呤抑制时，存活率降低。这些研究结果强调了细胞凋亡和自噬之间的重要相互作用，并提出了一种新的机制，Bcl-2，这是经常升高的淋巴恶性肿瘤，有助于糖皮质激素抵抗和生存的淋巴瘤细胞。
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.