College of Pharmacy, Third Military Medical University, Chongqing, 400038, China.
Cell Death Dis. 2018 Feb 14;9(2):243. doi: 10.1038/s41419-018-0276-8.
Increasing evidences reveal that autophagy inhibitor could enhance the effect of chemotherapy to cancer. However, few autophagy inhibitors are currently approved for clinical application in humans. Berbamine (BBM) is a natural compound extracted from traditional Chinese medicine that is widely used for treatment of a variety of diseases without any obvious side effects. Here we found that BBM is a novel auophagy inhibitor, which potently induced the accumulation of autophagosomes by inhibiting autophagosome-lysosome fusion in human breast cancer cells. Mechanistically, we found that BBM blocked autophagosome-lysosome fusion by inhibiting the interaction of SNAP29 and VAMP8. Furthermore, BBM induced upregulation of BNIP3 and the interaction between SNAP29 and BNIP3. BNIP3 depletion or SNAP29 overexpression abrogated BBM-mediated blockade of autophagosome-lysosome fusion through the interaction between SNAP29 and VAMP8, whereas BNIP3 overexpression blocked autophagosome-lysosome fusion through inhibition of the interaction between SNAP29 and VAMP8. These findings suggest that upregulation of BNIP3 and interaction between BNIP3 and SNAP29 could be involved in BBM-mediated blockade of autophagosome-lysosome fusion through inhibition of the interaction between SNAP29 and VAMP8. Our findings identify the critical role of BNIP3 in blockade of autophagosome-lysosome fusion mediated by BBM, and suggest that BBM could potentially be further developed as a novel autophagy inhibitor, which could enhance the effect of chemotherapy to cancer.
越来越多的证据表明，自噬抑制剂可以增强化疗对癌症的疗效。然而，目前临床上批准用于人类的自噬抑制剂很少。小檗胺（BBM）是一种从传统中药中提取的天然化合物，广泛用于治疗多种疾病，没有明显的副作用。在这里，我们发现 BBM 是一种新型的自噬抑制剂，它通过抑制自噬体-溶酶体融合，在人乳腺癌细胞中强烈诱导自噬体的积累。在机制上，我们发现 BBM 通过抑制 SNAP29 和 VAMP8 的相互作用来阻断自噬体-溶酶体融合。此外，BBM 诱导 BNIP3 的上调和 SNAP29 与 BNIP3 之间的相互作用。BNIP3 耗竭或 SNAP29 过表达通过 SNAP29 和 VAMP8 之间的相互作用，消除了 BBM 介导的自噬体-溶酶体融合的阻断，而 BNIP3 过表达通过抑制 SNAP29 和 VAMP8 之间的相互作用来阻断自噬体-溶酶体融合。这些发现表明，BNIP3 的上调和 BNIP3 与 SNAP29 之间的相互作用可能参与了 BBM 介导的通过抑制 SNAP29 和 VAMP8 之间的相互作用来阻断自噬体-溶酶体融合。我们的研究结果确定了 BNIP3 在 BBM 介导的自噬体-溶酶体融合阻断中的关键作用，并表明 BBM 可能作为一种新型自噬抑制剂进一步开发，从而增强化疗对癌症的疗效。
