Akt inhibition promotes autophagy and sensitizes PTEN-null tumors to lysosomotropic agents.
Akt inhibition promotes autophagy and sensitizes PTEN-null tumors to lysosomotropic agents.
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DOI：
10.1083/jcb.200801099
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发表时间：
2008-10-06
影响因子：
7.8
通讯作者：
Lin, Kui
中科院分区：
文献类型：
--
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
虽然Akt被认为是一种存活激酶，但磷脂酰肌醇3-激酶（PI 3 K）-Akt通路的抑制剂并不总是诱导大量的细胞凋亡。我们发现，沉默Akt 1单独，或任何组合的Akt亚型，可以抑制肿瘤的生长建立从磷酸酶和张力蛋白同源物无效的人类癌细胞。尽管这些发现表明Akt对于肿瘤维持是必不可少的，但大多数肿瘤最终会反弹。Akt敲低或小分子抑制剂失活不会诱导显著的细胞凋亡，但会显著增加自噬。进一步治疗与lysosomotropic剂氯喹引起异常的自噬溶酶体和活性氧的积累，导致加速细胞死亡在体外和体内肿瘤完全缓解。当Akt抑制与液泡H+-腺苷三磷酸酶抑制剂巴弗洛霉素A1或组织蛋白酶抑制相结合时，也促进了细胞死亡。这些结果表明，当自噬被激活时，阻断溶酶体降解可能对癌细胞存活有害，这为增强PI 3 K-Akt通路抑制的抗癌功效的新治疗方法提供了理论基础。
Although Akt is known as a survival kinase, inhibitors of the phosphatidylinositol 3-kinase (PI3K)–Akt pathway do not always induce substantial apoptosis. We show that silencing Akt1 alone, or any combination of Akt isoforms, can suppress the growth of tumors established from phosphatase and tensin homologue–null human cancer cells. Although these findings indicate that Akt is essential for tumor maintenance, most tumors eventually rebound. Akt knockdown or inactivation with small molecule inhibitors did not induce significant apoptosis but rather markedly increased autophagy. Further treatment with the lysosomotropic agent chloroquine caused accumulation of abnormal autophagolysosomes and reactive oxygen species, leading to accelerated cell death in vitro and complete tumor remission in vivo. Cell death was also promoted when Akt inhibition was combined with the vacuolar H+–adenosine triphosphatase inhibitor bafilomycin A1 or with cathepsin inhibition. These results suggest that blocking lysosomal degradation can be detrimental to cancer cell survival when autophagy is activated, providing rationale for a new therapeutic approach to enhancing the anticancer efficacy of PI3K–Akt pathway inhibition.
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影响因子：
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作者：
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