Targeting lactate dehydrogenase--a inhibits tumorigenesis and tumor progression in mouse models of lung cancer and impacts tumor-initiating cells.
Targeting lactate dehydrogenase--a inhibits tumorigenesis and tumor progression in mouse models of lung cancer and impacts tumor-initiating cells.
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DOI：
10.1016/j.cmet.2014.03.003
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发表时间：
2014-05-06
期刊：
影响因子：
29
通讯作者：
Seth P
中科院分区：
文献类型：
--
作者：
Xie H;Hanai J;Ren JG;Kats L;Burgess K;Bhargava P;Signoretti S;Billiard J;Duffy KJ;Grant A;Wang X;Lorkiewicz PK;Schatzman S;Bousamra M 2nd;Lane AN;Higashi RM;Fan TW;Pandolfi PP;Sukhatme VP;Seth P
乳酸脱氢酶a （LDH-A）催化丙酮酸和乳酸的相互转化，在人类癌症中表达上调，并与侵袭性肿瘤结果相关。在这里，我们使用了一种新的诱导小鼠模型，并证明了由致癌的K-RAS或EGFR驱动的非小细胞肺癌小鼠模型中ldl - a的失活导致肿瘤发生减少和已建立肿瘤的疾病消退。我们还表明，去除LDH-A会导致丙酮酸代谢的重编程，并在体外、体内和离体中减少乳酸发酵。这伴随着线粒体功能在体外的再激活，而不是在体内或离体。最后，使用一种特定的小分子ldl - a抑制剂，我们证明了ldl - a对癌症启动细胞的存活和增殖至关重要。因此，LDH-A可以成为包括癌症干细胞依赖性耐药肿瘤在内的非小细胞肺癌的可行治疗靶点。
The lactate dehydrogenase-A (LDH-A) enzyme catalyzes the inter-conversion of pyruvate and lactate, is upregulated in human cancers and is associated with aggressive tumor outcomes. Here we use a novel inducible murine model and demonstrate that inactivation of LDH-A in mouse models of NSCLC driven by oncogenic K-RAS or EGFR leads to decreased tumorigenesis and disease regression in established tumors. We also show that abrogation of LDH-A results in reprogramming of pyruvate metabolism, with decreased lactic fermentation in vitro, in vivo, and ex vivo. This was accompanied by re-activation of mitochondrial function in vitro but not in vivo or ex vivo. Finally, using a specific small molecule LDH-A inhibitor, we demonstrated that LDH-A is essential for cancer initiating cell survival and proliferation. Thus, LDH-A can be a viable therapeutic target for NSCLC including cancer stem cell-dependent drug resistant tumors.
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影响因子：
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Zhang, Xuying
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