Autophagy restricts proliferation driven by oncogenic phosphatidylinositol 3-kinase in three-dimensional culture.
Autophagy restricts proliferation driven by oncogenic phosphatidylinositol 3-kinase in three-dimensional culture.
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DOI：
10.1038/onc.2012.277
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发表时间：
2013-05-16
期刊：
影响因子：
8
通讯作者：
Debnath, J.
中科院分区：
文献类型：
--
作者：
Chen, N.;Eritja, N.;Lock, R.;Debnath, J.
自噬是一种受严格调控的溶酶体自身消化过程，可促进和阻碍肿瘤的发生。在这里，我们利用三维（3D）培养模型来解决自噬和PI3K/Akt/mTOR途径之间的相互作用如何影响携带肿瘤来源的PI3K激活突变（PI3K- h1047r）的细胞的恶性行为。在该模型中，自噬在单个腺体结构中同时介导肿瘤抑制和促进功能。在三维培养中，组成型PI3K激活克服了增殖阻滞，促进了对管腔腔内病变的抵抗，导致管腔内充满异常结构。抑制PI3K-H1047R结构的自噬触发管腔细胞凋亡，导致管腔清除。同时，ATG耗竭强烈增强了PI3K- h1047r细胞在3D形态发生过程中的增殖，揭示了自噬在PI3K激活驱动下抑制增殖的意想不到的作用。有趣的是，在PI3K-H1047R细胞中，自噬货物受体p62/SQSTM1的过表达足以增强细胞增殖，激活ERK/MAPK通路，并促进3D培养中不依赖egf的增殖。总的来说，这些结果表明，自噬拮抗致癌PI3K转化的特定方面，自噬的丧失促进增殖。
Autophagy is a tightly regulated lysosomal self-digestion process that can both promote and impede tumorigenesis. Here, we utilize a three-dimensional (3D) culture model to address how interactions between autophagy and the PI3K/Akt/mTOR pathway impact the malignant behavior of cells carrying a tumor-derived, activating mutation in PI3K (PI3K-H1047R). In this model, autophagy simultaneously mediates tumor suppressive and promoting functions within individual glandular structures. In 3D culture, constitutive PI3K activation overcomes proliferation arrest and promotes resistance to anoikis in the luminal space, resulting in aberrant structures with filled lumen. Inhibiting autophagy in PI3K-H1047R structures triggers luminal cell apoptosis, resulting in lumen clearance. At the same time, ATG depletion strongly enhances PI3K-H1047R cell proliferation during 3D morphogenesis, revealing an unexpected role for autophagy in restricting proliferation driven by PI3K activation. Intriguingly, over-expression of the autophagy cargo receptor p62/SQSTM1 in PI3K-H1047R cells is sufficient to enhance cell proliferation, activate the ERK/MAPK pathway, and to promote EGF-independent proliferation in 3D culture. Overall, these results indicate that autophagy antagonizes specific aspects of oncogenic PI3K transformation, with the loss of autophagy promoting proliferation.
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