Dual blockade of the lipid kinase PIP4Ks and mitotic pathways leads to cancer-selective lethality.
Dual blockade of the lipid kinase PIP4Ks and mitotic pathways leads to cancer-selective lethality.
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DOI：
10.1038/s41467-017-02287-5
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发表时间：
2017-12-19
影响因子：
16.6
通讯作者：
Lee SH
中科院分区：
文献类型：
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作者：
Kitagawa M;Liao PJ;Lee KH;Wong J;Shang SC;Minami N;Sampetrean O;Saya H;Lingyun D;Prabhu N;Diam GK;Sobota R;Larsson A;Nordlund P;McCormick F;Ghosh S;Epstein DM;Dymock BW;Lee SH
实现强大的癌症特异性致死率是最终的临床目标。在这里，我们鉴定了一种具有双重抑制特性的化合物，命名为a131，它可以选择性地杀死癌细胞，同时保护正常细胞。通过无偏的CETSA筛选，我们确定PIP4K脂质激酶是a131的靶标。PIP4Ks的消融产生了a131抑制PIP4K的药理学效应的表型。值得注意的是，a131对PIP4Ks的抑制通过转录上调PIK3IP1 （PI3K/Akt/mTOR通路的抑制因子）导致正常细胞可逆的生长停滞。引人注目的是，Ras激活覆盖了a131诱导的PIK3IP1上调，激活了PI3K/Akt/mTOR通路。因此，ras转化的细胞克服了a131诱导的生长停滞并进入有丝分裂，其中a131在癌细胞中去除多余中心体的能力通过有丝分裂灾难消除了ras激活的细胞。我们发现的具有双重抑制机制的药物提供了一种独特的抗癌药理策略，并证明了Ras/Raf/MEK/ERK和PI3K/AKT/mTOR通路通过Ras - PIK3IP1 - PI3K信号网络交叉激活。Ras/Raf/MEK/ERK和PI3K/Akt/mTOR信号通路对癌细胞存活至关重要。在这里，作者描述了一个具有双抑制特性的分子a131，它靶向PI5P4K和有丝分裂，参与Ras/Raf/MEK/ERK和PI3K/Akt/mTOR串扰，从而导致正常细胞可逆的生长停滞和肿瘤细胞死亡。
Achieving robust cancer-specific lethality is the ultimate clinical goal. Here, we identify a compound with dual-inhibitory properties, named a131, that selectively kills cancer cells, while protecting normal cells. Through an unbiased CETSA screen, we identify the PIP4K lipid kinases as the target of a131. Ablation of the PIP4Ks generates a phenocopy of the pharmacological effects of PIP4K inhibition by a131. Notably, PIP4Ks inhibition by a131 causes reversible growth arrest in normal cells by transcriptionally upregulating PIK3IP1, a suppressor of the PI3K/Akt/mTOR pathway. Strikingly, Ras activation overrides a131-induced PIK3IP1 upregulation and activates the PI3K/Akt/mTOR pathway. Consequently, Ras-transformed cells override a131-induced growth arrest and enter mitosis where a131’s ability to de-cluster supernumerary centrosomes in cancer cells eliminates Ras-activated cells through mitotic catastrophe. Our discovery of drugs with a dual-inhibitory mechanism provides a unique pharmacological strategy against cancer and evidence of cross-activation between the Ras/Raf/MEK/ERK and PI3K/AKT/mTOR pathways via a Ras˧PIK3IP1˧PI3K signaling network. The Ras/Raf/MEK/ERK and PI3K/Akt/mTOR signaling pathways are essential for cancer cell survival. Here, the authors describes a molecule a131 with dual-inhibitory properties, which targets PI5P4K and mitosis, and it is involved in Ras/Raf/MEK/ERK and PI3K/Akt/mTOR crosstalk, thereby causing reversible growth arrest in normal cells and cell death of tumor cells.
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影响因子：
4.1
作者：
Clarke, JH;Letcher, AJ;Divecha, N
通讯作者：
Divecha, N
影响因子：
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作者：
Bulley, Simon J;Clarke, Jonathan H;Droubi, Alaa;Giudici, Maria-Luisa;Irvine, Robin F
通讯作者：
Irvine, Robin F
影响因子：
4
作者：
Klaeger, Susan;Gohlke, Bjoern;Kuster, Bernhard
通讯作者：
Kuster, Bernhard
影响因子：
7.3
作者：
Mackey AM;Sarkes DA;Bettencourt I;Asara JM;Rameh LE
通讯作者：
Rameh LE
影响因子：
82.9
作者：
通讯作者：
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