CAMKK2 Promotes Prostate Cancer Independently of AMPK via Increased Lipogenesis.
CAMKK2 Promotes Prostate Cancer Independently of AMPK via Increased Lipogenesis.
复制标题
DOI：
10.1158/0008-5472.can-18-0585
复制
发表时间：
2018-12-15
期刊：
影响因子：
11.2
通讯作者：
Carling D
中科院分区：
文献类型：
--
作者：
Penfold L;Woods A;Muckett P;Nikitin AY;Kent TR;Zhang S;Graham R;Pollard A;Carling D
治疗前列腺癌，特别是去势抵抗性疾病需要新的靶点。先前的研究报道钙/钙调蛋白依赖性蛋白激酶激酶2（CAMKK 2）在人前列腺癌中表达增加。在这里，我们表明，Camkk 2删除或药理学抑制保护前列腺癌的发展在临床前小鼠模型，缺乏前列腺特异性磷酸酶和张力蛋白同源物（Pten）的表达。相反，AMP活化蛋白激酶（Ampk）β1的缺失导致腺癌发生的更早。这些发现首次表明Camkk 2和Ampk在前列腺癌进展中具有相反的作用。体内或人前列腺癌细胞中CAMKK 2的缺失降低了两种关键脂肪生成酶乙酰辅酶A羧化酶和脂肪酸合成酶的表达。这种减少是通过转录后机制介导的，可能涉及蛋白质翻译的减少。此外，CAMKK 2的缺失或AMPK的活化通过抑制从头脂肪生成来减少人前列腺癌细胞中的细胞生长。AMPK在一组人前列腺癌细胞中的激活抑制细胞增殖、迁移和侵袭以及雄激素受体信号传导。这些发现表明，CAMKK 2和AMPK对脂肪生成具有相反的作用，为它们在体内对前列腺癌进展的对比作用提供了潜在的机制。他们还表明，CAMKK 2的抑制与AMPK的激活相结合将为前列腺癌的治疗提供有效的治疗策略。
New targets are required for treating prostate cancer, particularly castrate-resistant disease. Previous studies reported that calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) expression is increased in human prostate cancer. Here we show that Camkk2 deletion or pharmacological inhibition protects against prostate cancer development in a pre-clinical mouse model that lacks expression of prostate-specific phosphatase and tensin homologue (Pten). In contrast, deletion of AMP-activated protein kinase (Ampk) β1 resulted in earlier onset of adenocarcinoma development. These findings suggest for the first time that Camkk2 and Ampk have opposing effects in prostate cancer progression. Loss of CAMKK2 in vivo or in human prostate cancer cells reduced the expression of two key lipogenic enzymes, acetyl-CoA carboxylase and fatty acid synthase. This reduction was mediated via a post-transcriptional mechanism, potentially involving a decrease in protein translation. Moreover, either deletion of CAMKK2 or activation of AMPK reduced cell growth in human prostate cancer cells by inhibiting de novo lipogenesis. Activation of AMPK in a panel of human prostate cancer cells inhibited cell proliferation, migration, and invasion as well as androgen-receptor signalling. These findings demonstrate that CAMKK2 and AMPK have opposing effects on lipogenesis, providing a potential mechanism for their contrasting effects on prostate cancer progression in vivo. They also suggest that inhibition of CAMKK2 combined with activation of AMPK would offer an efficacious therapeutic strategy in treatment of prostate cancer.