Niemann-Pick disease type C2 protein induces autophagy and inhibits growth in FM3A breast cancer cells
Niemann-Pick disease type C2 protein induces autophagy and inhibits growth in FM3A breast cancer cells
复制标题
DOI：
10.5582/ddt.2015.01014
复制
发表时间：
2015-08-01
影响因子：
3.1
通讯作者：
Sekimizu, Kazuhisa
中科院分区：
文献类型：
--
作者：
Adachi, Tatsuo;Matsumoto, Yasuhiko;Sekimizu, Kazuhisa
一些在昆虫和哺乳动物之间高度保守的肽具有抗肿瘤作用。从动物体液中筛选细胞生长抑制剂可能为抗肿瘤药物提供有用的线索。自噬诱导剂也具有抗肿瘤活性。目前的作者最近研究了一种在家蚕血淋巴中发现的蛋白质，尼曼-匹克病C2型（NPC 2）。这种蛋白质在真核生物中高度保守，被发现对家蚕细胞系具有抗增殖作用。目前的研究发现，家蚕NPC 2蛋白也抑制FM 3A小鼠乳腺癌细胞的生长。在FM 3A细胞中，蚕NPC 2增加AMP活化蛋白激酶的磷酸化，并减少Akt和雷帕霉素的哺乳动物靶点的磷酸化，这是自噬的调节剂。这项研究还发现，NPC 2增加了FM 3A细胞中微管相关蛋白轻链3（LC 3）-II（一种自噬体标记物）的量。家蚕NPC 2还诱导FM 3A细胞中LC 3-点（自噬前内体的标志物）数量的增加。当蚕NPC 2用于抑制FM 3A细胞生长时，氯喹减弱了该抑制作用，氯喹通过防止溶酶体酸化来抑制自噬活性。鼠NPC 2还抑制生长并诱导FM 3A细胞中的自噬。这些发现表明，NPC 2参与诱导和/或维持自噬，并可能有助于阐明其他神经退行性疾病（如尼曼-皮克病）的潜在机制。
Some peptides that are highly conserved between insects and mammals have anti-tumor action. Screening for inhibitors of cell growth from animal fluids may provide useful clues to anti-tumor drugs. Inducers of autophagy also have anti-tumor activity. The current authors recently studied a protein found in silkworm hemolymph, Niemann-Pick disease type C2 (NPC2). This protein, which is highly conserved among eukaryotes, was found to have anti-proliferative action on a silkworm cell line. The current study found that the silkworm NPC2 protein also inhibits the growth of FM3A murine breast cancer cells. In FM3A cells, silkworm NPC2 increased phosphorylation of AMP-activated protein kinase and decreased phosphorylation of Akt and mammalian target of rapamycin, which are regulators of autophagy. This study also found that NPC2 increased the amount of microtubule-associated protein light chain 3 (LC3)-II, an autophagosome marker, in FM3A cells. Silkworm NPC2 also induced an increase in the number of LC3-dots, a marker of pre-autophagic endosomes, in FM3A cells. When silkworm NPC2 was used to inhibit FM3A cell growth, that inhibition was attenuated by chloroquine, which inhibits autophagic activity by preventing lysosomal acidification. Murine NPC2 also inhibited growth and induced autophagy in FM3A cells. These findings suggest that NPC2 is involved in the induction and/or maintenance of autophagy and may help to elucidate the mechanisms underlying other neurodegenerative disorders such as Niemann-Pick disease.