Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression
Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression
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DOI：
10.1073/pnas.0914433107
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发表时间：
2010-02-02
影响因子：
11.1
通讯作者：
Dang, Chi V.
中科院分区：
文献类型：
--
作者：
Le, Anne;Cooper, Charles R.;Dang, Chi V.
由于基因改变和肿瘤缺氧，许多癌细胞大量摄取葡萄糖，并通过乳酸脱氢酶A （LDHA）生成乳酸，乳酸脱氢酶A由c-Myc靶基因和缺氧诱导因子（HIF-1）编码。以往关于LDHA表达降低的研究表明，LDHA参与了肿瘤的发生，但其在肿瘤维持和进展中的作用尚未确定。此外，通过干扰或反义RNA减少LDHA表达如何抑制肿瘤发生尚不清楚。在这里，我们报告了siRNA或小分子抑制剂（FX11[3-二羟基-6-甲基-7-（苯基甲基）-4-丙基萘-1-羧酸]）对LDHA的抑制作用降低了ATP水平，并诱导了显著的氧化应激和细胞死亡，这可以通过抗氧化剂n -乙酰半胱氨酸部分逆转。此外，我们发现FX11抑制了相当大的人淋巴瘤和胰腺癌异种移植的进展。当与NAD（+）合成抑制剂FK866联合使用时，FX11诱导淋巴瘤消退。因此，FX11抑制LDHA对LDHA依赖性肿瘤是一种可实现且可耐受的治疗方法。我们的研究记录了Warburg效应的治疗方法，并证明了癌症的氧化应激和代谢表型是癌症生物学的关键方面，可以考虑癌症能量代谢的治疗靶向。
As the result of genetic alterations and tumor hypoxia, many cancer cells avidly take up glucose and generate lactate through lactate dehydrogenase A (LDHA), which is encoded by a target gene of c-Myc and hypoxia-inducible factor (HIF-1). Previous studies with reduction of LDHA expression indicate that LDHA is involved in tumor initiation, but its role in tumor maintenance and progression has not been established. Furthermore, how reduction of LDHA expression by interference or antisense RNA inhibits tumorigenesis is not well understood. Here, we report that reduction of LDHA by siRNA or its inhibition by a small-molecule inhibitor (FX11 [3-dihydroxy-6-methyl-7-(phenylmethyl)-4-propylnaphthalene-1-carboxylic acid]) reduced ATP levels and induced significant oxidative stress and cell death that could be partially reversed by the antioxidant N-acetylcysteine. Furthermore, we document that FX11 inhibited the progression of sizable human lymphoma and pancreatic cancer xenografts. When used in combination with the NAD(+) synthesis inhibitor FK866, FX11 induced lymphoma regression. Hence, inhibition of LDHA with FX11 is an achievable and tolerable treatment for LDHA-dependent tumors. Our studies document a therapeutical approach to the Warburg effect and demonstrate that oxidative stress and metabolic phenotyping of cancers are critical aspects of cancer biology to consider for the therapeutical targeting of cancer energy metabolism.