Basal autophagy is pivotal for Hodgkin and Reed-Sternberg cells' survival and growth revealing a new strategy for Hodgkin lymphoma treatment.
Basal autophagy is pivotal for Hodgkin and Reed-Sternberg cells' survival and growth revealing a new strategy for Hodgkin lymphoma treatment.
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DOI：
10.18632/oncotarget.10300
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发表时间：
2016-07-19
期刊：
影响因子：
--
通讯作者：
Hansmann ML
中科院分区：
文献类型：
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作者：
Birkenmeier K;Moll K;Newrzela S;Hartmann S;Dröse S;Hansmann ML
由于目前经典的霍奇金淋巴瘤（cHL）治疗策略具有明显的副作用，特异性抑制信号通路可能为cHL治疗提供新的策略。基础自噬是一种降解细胞自身成分的受调节的分解代谢途径，在癌症中与肿瘤抑制或促进两者相关。因此，基础自噬增强肿瘤细胞存活的发现将导致立即可测试的新疗法策略。因此，我们研究了它在cHL中的贡献。我们在cHL细胞系和原代组织中发现了自噬的组成性激活。关键自噬相关蛋白（例如Beclin-1，ULK 1）和LC 3加工的表达在cHL细胞中增加，即使在淋巴瘤病例中也是如此。一致地，cHL细胞表现出增加的自噬空泡数量和完整的自噬通量。自噬抑制氯喹或ATG 5的失活诱导细胞凋亡和减少cHL细胞的增殖。氯喹介导的基础自噬抑制显著损害NOD SCID γc−/−（NSG）小鼠体内HL生长。我们发现基础自噬在维持线粒体功能中起着关键作用。我们的结论是，cHL细胞需要基础自噬的生长，生存和持续的代谢，使他们敏感的自噬抑制。这表明基础自噬是cHL治疗新策略的有用靶标。
As current classical Hodgkin lymphoma (cHL) treatment strategies have pronounced side-effects, specific inhibition of signaling pathways may offer novel strategies in cHL therapy. Basal autophagy, a regulated catabolic pathway to degrade cell's own components, is in cancer linked with both, tumor suppression or promotion. The finding that basal autophagy enhances tumor cell survival would thus lead to immediately testable strategies for novel therapies. Thus, we studied its contribution in cHL. We found constitutive activation of autophagy in cHL cell lines and primary tissue. The expression of key autophagy-relevant proteins (e.g. Beclin-1, ULK1) and LC3 processing was increased in cHL cells, even in lymphoma cases. Consistently, cHL cells exhibited elevated numbers of autophagic vacuoles and intact autophagic flux. Autophagy inhibition with chloroquine or inactivation of ATG5 induced apoptosis and reduced proliferation of cHL cells. Chloroquine-mediated inhibition of basal autophagy significantly impaired HL growth in-vivo in NOD SCID γc−/− (NSG) mice. We found that basal autophagy plays a pivotal role in sustaining mitochondrial function. We conclude that cHL cells require basal autophagy for growth, survival and sustained metabolism making them sensitive to autophagy inhibition. This suggests basal autophagy as useful target for new strategies in cHL treatment.