Cryptotanshinone inhibition of mammalian target of rapamycin pathway is dependent on oestrogen receptor alpha in breast cancer.
Cryptotanshinone inhibition of mammalian target of rapamycin pathway is dependent on oestrogen receptor alpha in breast cancer.
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隐丹参酮对哺乳动物雷帕霉素途径靶标的抑制依赖于乳腺癌中的雌激素受体α
DOI：
10.1111/jcmm.13135
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发表时间：
2017-09
影响因子：
5.3
通讯作者：
Lu Y
中科院分区：
文献类型：
--
作者：
Pan Y;Shi J;Ni W;Liu Y;Wang S;Wang X;Wei Z;Wang A;Chen W;Lu Y
隐丹参酮（CPT）已被证明可以抑制MCF-7乳腺癌细胞的增殖和哺乳动物雷帕霉素靶蛋白（mTOR）通路。然而，在MDA-MB-231细胞中不能重复相同的结果。鉴于两种乳腺癌细胞雌激素受体α（ER α）的主要差异，提示CPT可能抑制乳腺癌中依赖于ER α的mTOR通路。CPT可显著抑制ER α阳性癌细胞的细胞增殖，而ER α阴性癌细胞对CPT不敏感。分子对接结果表明CPT与ER α具有高亲和力，雌激素受体元件荧光素酶报告基因证实CPT具有明显的抗雌激素作用。此外，CPT抑制MCF-7细胞中的mTOR信号传导，但不抑制MDA-MB-231细胞中的mTOR信号传导，这不依赖于与FKBP12的结合和破坏mTOR复合物。同时，CPT可拮抗胰岛素样生长因子1（IGF-1）诱导的磷酸化AKT和胰岛素受体底物（IRS1）的表达增加，但对IGF-1/AKT/mTOR信号通路的其他分子如磷酸酶和张力蛋白同源物（PTEN）和磷脂酰肌醇-4，5-二磷酸3-激酶（PI3K）产生负面影响。最后，用shER α转染以沉默ER α的MCF-7细胞显示出对CPT的抗性，并且p-AKT、p70 S6激酶1（p-S6K1）和真核起始因子4E结合蛋白1（4E-BP1）的磷酸化部分恢复，这表明ER α是CPT抑制mTOR信号传导所必需的。总的来说，CPT对mTOR的抑制依赖于乳腺癌中的ER α，应该是一种潜在的抗雌激素药物和应用于内分泌抵抗治疗的天然佐剂。
Cryptotanshinone (CPT) has been demonstrated to inhibit proliferation and mammalian target of rapamycin (mTOR) pathway in MCF‐7 breast cancer cells. However, the same results are unable to be repeated in MDA‐MB‐231 cells. Given the main difference of oestrogen receptor α (ERα) between two types of breast cancer cells, It is possibly suggested that CPT inhibits mTOR pathway dependent on ERα in breast cancer. CPT could significantly inhibit cell proliferation of ERα‐positive cancer cells, whereas ERα‐negative cancer cells are insensitive to CPT. The molecular docking results indicated that CPT has a high affinity with ERα, and the oestrogen receptor element luciferase reporter verified CPT distinct anti‐oestrogen effect. Furthermore, CPT inhibits mTOR signalling in MCF‐7 cells, but not in MDA‐MB‐231 cells, which is independent on binding to the FKBP12 and disrupting the mTOR complex. Meanwhile, increased expression of phosphorylation AKT and insulin receptor substrate (IRS1) induced by insulin‐like growth factor 1 (IGF‐1) was antagonized by CPT, but other molecules of IGF‐1/AKT/mTOR signalling pathway such as phosphatase and tensin homolog (PTEN) and phosphatidylinositol‐4,5‐bisphosphate 3‐kinase (PI3K) were negatively affected. Finally, the MCF‐7 cells transfected with shERα for silencing ERα show resistant to CPT, and p‐AKT, phosphorylation of p70 S6 kinase 1 (p‐S6K1) and eukaryotic initiation factor 4E binding protein 1 (4E‐BP1) were partially recovered, suggesting ERα is required for CPT inhibition of mTOR signalling. Overall, CPT inhibition of mTOR is dependent on ERα in breast cancer and should be a potential anti‐oestrogen agent and a natural adjuvant for application in endocrine resistance therapy.
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影响因子：
11.2
作者：
Miller TW;Pérez-Torres M;Narasanna A;Guix M;Stål O;Pérez-Tenorio G;Gonzalez-Angulo AM;Hennessy BT;Mills GB;Kennedy JP;Lindsley CW;Arteaga CL
通讯作者：
Arteaga CL
影响因子：
2.8
作者：
Chen W;Lu Y;Chen G;Huang S
通讯作者：
Huang S
影响因子：
3.1
作者：
Cleator, Susan J.;Ahamed, Eliyaz;Palmieri, Carlo
通讯作者：
Palmieri, Carlo
影响因子：
11.2
作者：
Kang, Hyun-Jin;Lee, Min-Ho;Lee, Mi-Ock
通讯作者：
Lee, Mi-Ock
影响因子：
3.6
作者：
Kim, Eun Ju;Jung, Seung-Nam;Ha, Joohun
通讯作者：
Ha, Joohun