mTOR complex-2 stimulates acetyl-CoA and de novo lipogenesis through ATP citrate lyase in HER2/PIK3CA-hyperactive breast cancer.
mTOR complex-2 stimulates acetyl-CoA and de novo lipogenesis through ATP citrate lyase in HER2/PIK3CA-hyperactive breast cancer.
复制标题
mTOR 复合物 2 在 HER2/PIK3CA 过度活跃乳腺癌中通过 ATP 柠檬酸裂解酶刺激乙酰辅酶 A 和从头脂肪生成
DOI：
10.18632/oncotarget.8279
复制
发表时间：
2016-05-03
期刊：
影响因子：
--
通讯作者：
Yu K
中科院分区：
文献类型：
--
作者：
Chen Y;Qian J;He Q;Zhao H;Toral-Barza L;Shi C;Zhang X;Wu J;Yu K
雷帕霉素的机制靶点（mTOR）是细胞生长的主要调节因子，在癌症中经常失调。虽然mTOR复合物-1 （mTORC1）是一个经过验证的癌症靶点，但mTOR复合物-2 （mTORC2）的作用仍然不太明确。在这里，我们发现mTORC2是乳腺癌代谢的关键调节因子。我们发现ATP柠檬酸裂解酶（ACL）的过度磷酸化在人类乳腺肿瘤中经常发生，并且与乳腺肿瘤细胞系中HER2+和/或pik3ca突变体（HER2+/PIK3CAmut）状态密切相关。在HER2+/PIK3CAmut细胞中，mTORC2控制ACL的Ser-455磷酸化，从而促进乙酰辅酶a的产生、新生脂肪生成和线粒体生理，所有这些都被mTORC1/mTORC2激酶抑制剂（mTOR-KI）或mTORC2或ACL的细胞耗尽所抑制。mTOR-KI而非雷帕霉素阻断了igf -1诱导的ACL磷酸化和葡萄糖到脂质的转化。mTORC2而非mTORC1的缺失特异性地抑制了acl依赖性乙酰辅酶a的产生。在HER2+/PIK3CAmut MDA361、MDA453、BT-474和T47D细胞中，mTORC2或ACL的缺失导致生长抑制和线粒体超极化，这部分被乙酰辅酶a的替代来源所拯救。这些相同的变化在mTORC2或acl缺失的HER2-/PIK3CAwt MDA231和HCC1806细胞中并不明显，这突出了mTORC2- acl对这两种细胞类型存活的差异依赖性。此外，ACL Ser-455突变体S455E（拟磷酸化）和S455A（非磷酸化）分别增加或降低了乙酰辅酶a的产生，线粒体稳态和存活在ACL缺失的MDA453细胞中。这些研究确定了mTORC1 - acl在脂肪生成和乙酰辅酶a生物学中的新的雷帕霉素耐药机制，并为靶向mTORC1和mTORC2治疗HER2+/PIK3CAmut乳腺癌提供了理论依据。
The mechanistic target of rapamycin (mTOR) is a major regulator of cell growth and is frequently dysregulated in cancer. While mTOR complex-1 (mTORC1) is a validated cancer target, the role of mTOR complex-2 (mTORC2) remains less defined. Here, we reveal mTORC2 as a critical regulator of breast cancer metabolism. We showed that hyperphosphorylation in ATP citrate lyase (ACL) occurs frequently in human breast tumors and correlates well with HER2+ and/or PIK3CA-mutant (HER2+/PIK3CAmut) status in breast tumor cell lines. In HER2+/PIK3CAmut cells, mTORC2 controls Ser-455 phosphorylation of ACL thereby promoting acetyl-CoA production, de novo lipogenesis and mitochondrial physiology, all of which were inhibited by an mTORC1/mTORC2 kinase inhibitor (mTOR-KI) or cellular depletion of mTORC2 or ACL. mTOR-KI but not rapamycin blocked the IGF-1-induced ACL phosphorylation and glucose to lipid conversion. Depletion of mTORC2 but not mTORC1 specifically inhibited the ACL-dependent acetyl-CoA production. In the HER2+/PIK3CAmut MDA361, MDA453, BT-474 and T47D cells, depletion of mTORC2 or ACL led to growth inhibition and mitochondrial hyperpolarization, which were partially rescued by an alternate source of acetyl-CoA. These same changes were not apparent in mTORC2- or ACL-depleted HER2-/PIK3CAwt MDA231 and HCC1806 cells, highlighting a differential dependence of mTORC2-ACL for survival in these two cell types. Moreover, ACL Ser-455 mutants S455E (phosphomimetic) and S455A (non-phosphorylatable) each increased or decreased, respectively, the acetyl-CoA production, mitochondrial homeostasis and survival in ACL-depleted MDA453 cells. These studies define a new and rapamycin-resistant mechanism of mTORC2-ACL in lipogenesis and acetyl-CoA biology and provide a rationale for targeting of mTORC1 and mTORC2 in HER2+/PIK3CAmut breast cancer.
登录
查看更多内容
影响因子：
29
作者：
Lee JV;Carrer A;Shah S;Snyder NW;Wei S;Venneti S;Worth AJ;Yuan ZF;Lim HW;Liu S;Jackson E;Aiello NM;Haas NB;Rebbeck TR;Judkins A;Won KJ;Chodosh LA;Garcia BA;Stanger BZ;Feldman MD;Blair IA;Wellen KE
通讯作者：
Wellen KE
影响因子：
--
作者：
Leontieva OV;Demidenko ZN;Blagosklonny MV
通讯作者：
Blagosklonny MV
影响因子：
28.2
作者：
Cheng H;Zou Y;Ross JS;Wang K;Liu X;Halmos B;Ali SM;Liu H;Verma A;Montagna C;Chachoua A;Goel S;Schwartz EL;Zhu C;Shan J;Yu Y;Gritsman K;Yelensky R;Lipson D;Otto G;Hawryluk M;Stephens PJ;Miller VA;Piperdi B;Perez-Soler R
通讯作者：
Perez-Soler R
各种各样的癌症相关MTOR突变是过度激活的，可以预测雷帕霉素的敏感性。
影响因子：
28.2
作者：
Grabiner BC;Nardi V;Birsoy K;Possemato R;Shen K;Sinha S;Jordan A;Beck AH;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
8.8
作者：
Mashima, T.;Seimiya, H.;Tsuruo, T.
通讯作者：
Tsuruo, T.