CaM kinase kinase beta-mediated activation of the growth regulatory kinase AMPK is required for androgen-dependent migration of prostate cancer cells.
CaM kinase kinase beta-mediated activation of the growth regulatory kinase AMPK is required for androgen-dependent migration of prostate cancer cells.
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DOI：
10.1158/0008-5472.can-10-2581
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发表时间：
2011-01-15
期刊：
影响因子：
11.2
通讯作者：
McDonnell DP
中科院分区：
文献类型：
--
作者：
Frigo DE;Howe MK;Wittmann BM;Brunner AM;Cushman I;Wang Q;Brown M;Means AR;McDonnell DP
虽然晚期前列腺癌患者最初对雄激素消融治疗反应良好，但大多数患者在1-2年内复发。虽然难治性疾病对雄激素剥夺无反应，但雄激素受体（AR）调节的信号通路仍然活跃，并且是癌症进展所必需的。因此，AR本身和受体下游的过程仍然是治疗干预的可行靶标。多个临床队列的微阵列分析显示，丝氨酸/苏氨酸激酶Ca 2 +/钙调蛋白依赖性蛋白激酶激酶β（CaMKKβ）在前列腺中高度表达，并在前列腺癌中进一步升高。使用前列腺癌的细胞模型，我们已经确定雄激素1）直接增加CaMKKβ剪接变体的表达，2）增加功能性CaMKKβ蛋白水平，如通过CaMKI和AMP活化蛋白激酶（AMPK）（CaMKKβ的两种主要底物）的磷酸化所确定的。重要的是，通过药理学抑制剂或siRNA介导的敲低抑制前列腺癌细胞中的CaMKKβ-AMPK而不是CaMKI信号传导轴，阻断雄激素介导的迁移和侵袭。相反，CaMKKβ单独过表达导致AMPK磷酸化和细胞迁移增加。鉴于CaMKKβ和AMPK在前列腺癌细胞生物学中的关键作用，我们认为这些酶是前列腺癌的潜在治疗靶点。
While patients with advanced prostate cancer initially respond favorably to androgen ablation therapy, most experience a relapse of the disease within 1–2 years. Although hormone-refractory disease is unresponsive to androgen-deprivation, androgen receptor (AR)-regulated signaling pathways remain active and are necessary for cancer progression. Thus, both AR itself and the processes downstream of the receptor remain viable targets for therapeutic intervention. Microarray analysis of multiple clinical cohorts showed that the serine/threonine kinase Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ) is both highly expressed in the prostate and further elevated in prostate cancers. Using cellular models of prostate cancer, we have determined that androgens 1) directly increase the expression of a CaMKKβ splice variant and 2) increase functional CaMKKβ protein levels as determined by the phosphorylation of both CaMKI and AMP-activated protein kinase (AMPK), two of CaMKKβ’s primary substrates. Importantly, inhibition of the CaMKKβ-AMPK, but not CaMKI, signaling axis in prostate cancer cells by pharmacological inhibitors or siRNA-mediated knockdown blocks androgen-mediated migration and invasion. Conversely, overexpression of CaMKKβ alone leads to both increased AMPK phosphorylation and cell migration. Given the key roles of CaMKKβ and AMPK in the biology of prostate cancer cells, we propose that these enzymes are potential therapeutic targets in prostate cancer.