Cancerous inhibitor of protein phosphatase 2A mediates bortezomib-induced autophagy in hepatocellular carcinoma independent of proteasome.
Cancerous inhibitor of protein phosphatase 2A mediates bortezomib-induced autophagy in hepatocellular carcinoma independent of proteasome.
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DOI：
10.1371/journal.pone.0055705
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Chen KF
中科院分区：
文献类型：
--
作者：
Yu HC;Hou DR;Liu CY;Lin CS;Shiau CW;Cheng AL;Chen KF
以前，我们报道了蛋白磷酸酶2A（CIP 2A）的癌性抑制剂介导硼替佐米在肝细胞癌（HCC）中的凋亡作用。在这里，我们报告了一个蛋白酶体独立的机制，硼替佐米诱导肝癌细胞自噬。我们的数据表明，硼替佐米在HCC细胞系（包括Huh-7、Sk-Hep 1和Hep 3B）中以剂量和时间依赖性方式激活自噬。硼替佐米在所有测试的HCC细胞中以剂量和时间依赖性方式下调CIP 2A、磷酸化Akt（P-Akt）和磷酸化-4EBP 1（P-4 EBP 1）。CIP 2A的异位表达消除了硼替佐米对自噬的影响。硼替佐米和calyculin A（一种PP 2A抑制剂）的联合治疗降低了硼替佐米对P-Akt、P-4 EBP 1和自噬的影响。通过异位过表达增加Akt或4 EBP 1的磷酸化保护细胞免受硼替佐米诱导的自噬。此外，我们研究了ΔBtz在HCC中的作用，Δ Btz是一种硼替佐米衍生物，其结构与硼替佐米非常相似，但没有蛋白酶体活性。有趣的是，ΔBtz对自噬、CIP 2A、P-Akt和P-4 EBP 1的作用与硼替佐米相似，表明硼替佐米对自噬的作用不依赖于蛋白酶体抑制。此外，我们的体内数据显示硼替佐米和ΔBtz均抑制肿瘤生长，下调CIP 2A，P-Akt并诱导Huh-7肿瘤中的自噬。总之，硼替佐米通过CIP 2A-PP 2A-Akt-4 EBP 1途径诱导HCC中的自噬。
Previously, we reported that cancerous inhibitor of protein phosphatase 2A (CIP2A) mediates the apoptotic effect of bortezomib in hepatocellular carcinoma (HCC). Here, we report a proteasome-independent mechanism by which bortezomib induces autophagy in HCC. Our data indicate that bortezomib activated autophagy in a dose- and time- dependent manner in HCC cell lines including Huh-7, Sk-Hep1, and Hep3B. Bortezomib downregulated CIP2A, phospho-Akt (P-Akt) and phospho-4EBP1 (P-4EBP1) in a dose- and time-dependent manner in all tested HCC cells. Ectopic expression of CIP2A abolished the effect of bortezomib on autophagy. Co-treatment of bortezomib and calyculin A, a PP2A inhibitor, reduced the effect of bortezomib on P-Akt, P-4EBP1, and autophagy. Increased phosphorylation of either Akt or 4EBP1 by ectopic overexpression protected cells from bortezomib-induced autophagy. Furthermore, we examined the effect of ΔBtz, a bortezomib derivative that closely resembles bortezomib structurally but has no proteasome activity, in HCC. Interestingly, ΔBtz demonstrated similar effects to bortezomib on autophagy, CIP2A, P-Akt and P-4EBP1, suggesting that the effect of bortezomib on autophagy is independent of proteasome inhibition. Moreover, our in vivo data showed that both bortezomib and ΔBtz inhibited tumor growth, downregulated CIP2A, P-Akt and induced autophagy in Huh-7 tumors. In conclusion, bortezomib induces autophagy in HCC through a CIP2A-PP2A-Akt-4EBP1 pathway.
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影响因子：
11.2
作者：
Fels DR;Ye J;Segan AT;Kridel SJ;Spiotto M;Olson M;Koong AC;Koumenis C
通讯作者：
Koumenis C
影响因子：
7.8
作者：
Degtyarev, Michael;De Maziere, Ann;Orr, Christine;Lin, Jie;Lee, Brian B.;Tien, Janet Y.;Prior, Wei W.;van Dijk, Suzanne;Wu, Hong;Gray, Daniel C.;Davis, David P.;Stern, Howard M.;Murray, Lesley J.;Hoeflich, Klaus P.;Klumperman, Judith;Friedman, Lori S.;Lin, Kui
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Lin, Kui
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11.5
作者：
Come, Christophe;Laine, Anni;Westermarck, Jukka
通讯作者：
Westermarck, Jukka
影响因子：
11.2
作者：
Chen, Kuen-Feng;Yeh, Pei-Yen;Cheng, Ann-Lii
通讯作者：
Cheng, Ann-Lii
影响因子：
3.7
作者：
Dong, Qian-Ze;Wang, Yang;Wang, En-Hua
通讯作者：
Wang, En-Hua