IBP-mediated suppression of autophagy promotes growth and metastasis of breast cancer cells via activating mTORC2/Akt/FOXO3a signaling pathway.
IBP-mediated suppression of autophagy promotes growth and metastasis of breast cancer cells via activating mTORC2/Akt/FOXO3a signaling pathway.
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IBP介导的自噬抑制通过激活mTORC2/Akt/FOXO3a信号通路促进乳腺癌细胞的生长和转移
DOI：
10.1038/cddis.2013.380
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发表时间：
2013-10-10
影响因子：
9
通讯作者：
Li, S.
中科院分区：
文献类型：
--
作者：
Chen, S.;Han, Q.;Wang, X.;Yang, M.;Zhang, Z.;Li, P.;Chen, A.;Hu, C.;Li, S.
关键词：
干扰素调节因子-4结合蛋白（Interferon regulatory factor-4 binding protein，IBP）是Rho GTPases的一种新的上游激活因子。我们前期的研究表明，IBP的异位表达与人乳腺癌细胞的恶性行为相关，浸润性乳腺癌中存在IBP的高表达，促进了这些细胞的增殖。然而，自噬抑制是否有助于IBP介导的肿瘤发生仍然是未知的。在这项研究中，我们首次报道了IBP表达上调显著抑制乳腺癌细胞的自噬，而IBP表达下调显著诱导这些细胞的自噬。进一步的研究表明，IBP通过直接激活哺乳动物雷帕霉素靶蛋白复合物2（mTORC 2）和上调丝氨酸473上Akt和Thr 32上FOXO 3a的磷酸化，有效地抵消了自噬。此外，IBP介导的自噬抑制依赖于mTORC 2/Akt/FOXO 3a信号通路。最后，我们的研究结果表明，IBP介导的乳腺癌细胞在体外和体内的生长与mTORC 2依赖性自噬的抑制密切相关。这些结果表明，抗自噬的特性有一个重要的作用，在IBP介导的肿瘤，IBP可能作为一个有吸引力的靶点治疗乳腺癌。
Interferon regulatory factor-4 binding protein (IBP) is a novel upstream activator of Rho GTPases. Our previous studies have shown that ectopic expression of IBP was correlated with malignant behaviors of human breast cancer cells, and invasive human breast cancer had high expression of IBP that promoted the proliferation of these cells. However, it remains unknown whether autophagy inhibition contributes to IBP-mediated tumorigenesis. In this study, we for the first time, reported that upregulation of IBP expression significantly suppressed the autophagy of breast cancer cells, and downregulation of IBP expression markedly induced autophagy of these cells. Further investigation revealed that IBP effectively counteracted autophagy by directly activating mammalian target of rapamycin complex 2 (mTORC2) and upregulating phosphorylation of Akt on ser473 and FOXO3a on Thr32. Moreover, IBP-mediated suppression of autophagy was dependent on mTORC2/Akt/FOXO3a signaling pathway. Finally, our results demonstrated that IBP-mediated breast cancer cell growth in vitro and in vivo was strongly correlated with suppression of mTORC2-dependent autophagy. These findings suggest that the anti-autophagic property of IBP has an important role in IBP-mediated tumorigenesis, and IBP may serve as an attractive target for treatment of breast cancer.
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影响因子：
15.9
作者：
Becart, Stephane;Charvet, Celine;Altman, Amnon
通讯作者：
Altman, Amnon
影响因子：
13.3
作者：
Akar, Ugur;Chaves-Reyez, Arturo;Ozpolat, Bulent
通讯作者：
Ozpolat, Bulent
影响因子：
11.5
作者：
Amaravadi, Ravi K.;Thompson, Craig B.
通讯作者：
Thompson, Craig B.
影响因子：
5.7
作者：
Bhagwat, Shripad V.;Gokhale, Prafulla C.;Pachter, Jonathan A.
通讯作者：
Pachter, Jonathan A.
DOI：
10.4049/jimmunol.0902573
发表时间：
2009-12-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Canonigo-Balancio AJ;Fos C;Prod'homme T;Bécart S;Altman A
通讯作者：
Altman A