AMP-activated protein kinase promotes human prostate cancer cell growth and survival.
AMP-activated protein kinase promotes human prostate cancer cell growth and survival.
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DOI：
10.1158/1535-7163.mct-08-0631
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发表时间：
2009-04
影响因子：
5.7
通讯作者：
Collins SP
中科院分区：
文献类型：
--
作者：
Park HU;Suy S;Danner M;Dailey V;Zhang Y;Li H;Hyduke DR;Collins BT;Gagnon G;Kallakury B;Kumar D;Brown ML;Fornace A;Dritschilo A;Collins SP
前列腺癌发生发展的分子机制目前还知之甚少。AMP激活的蛋白激酶(AMPK)是一种丝氨酸-苏氨酸激酶，在人类前列腺癌中发现的缺氧条件下被激活。在能量耗竭的情况下，AMPK的激活促进代谢变化，以维持细胞的增殖和生存。在这里，我们报告了在人类前列腺癌中普遍存在的AMPK的激活，并提供了抑制或耗尽AMPK导致细胞增殖减少和细胞死亡增加的证据。在接受检查的人前列腺癌标本中，有40%的AMPK高度激活。内源性AMPK在雄激素敏感的LNCaP细胞和雄激素非依赖性的人前列腺癌CWR22Rv1细胞中均有活性。通过siRNA耗尽AMPK催化亚基或用小分子AMPK抑制剂(化合物C)抑制AMPK活性可抑制人前列腺癌细胞的增殖。在抑制AMPK活性的化合物C浓度下，可诱导LNCaP和CWR22Rv1细胞发生凋亡。这是首次报道激活的AMPK通路参与人前列腺癌的生长和生存，并为人类前列腺癌的化学预防提供了新的潜在靶点。
The molecular mechanisms underlying the development and progression of prostate cancer are poorly understood. AMP-activated protein kinase (AMPK) is a serine-threonine kinase that is activated in response to the hypoxic conditions found in human prostate cancers. In response to energy depletion, AMPK activation promotes metabolic changes to maintain cell proliferation and survival. Here, we report prevalent activation of AMPK in human prostate cancers and provide evidence that inhibition or depletion of AMPK leads to decreased cell proliferation and increased cell death. AMPK was highly activated in 40% of human prostate cancer specimens examined. Endogenous AMPK was active in both the androgen-sensitive LNCap cells and the androgen-independent CWR22Rv1 human prostate cancer cells. Depletion of AMPK catalytic subunits by siRNA or inhibition of AMPK activity with a small molecule AMPK inhibitor (compound C) suppresses human prostate cancer cell proliferation. Apoptotic cell death was induced in LNCap and CWR22Rv1 cells at compound C concentrations that inhibited AMPK activity. The evidence provided here is the first report that the activated AMPK pathway is involved in the growth and survival of human prostate cancer and offers novel potential targets for chemoprevention of human prostate cancer.