Survival advantage of AMPK activation to androgen-independent prostate cancer cells during energy stress.
Survival advantage of AMPK activation to androgen-independent prostate cancer cells during energy stress.
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DOI：
10.1016/j.cellsig.2010.05.024
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发表时间：
2010-10
影响因子：
4.8
通讯作者：
Ip C
中科院分区：
文献类型：
--
作者：
Chhipa RR;Wu Y;Mohler JL;Ip C
雄激素非依赖性前列腺癌通常在雄激素消融治疗后复发。全身性去除雄激素会导致前列腺肿瘤组织的血管变性和营养耗尽。恶性肿瘤后来演变为雄激素依赖性的事实表明，一些癌细胞能够在能量/营养剥夺的挑战中生存下来。AMP激活蛋白激酶（AMPK）是能量应激的重要管理者。本研究旨在研究AMPK在促进雄激素非依赖性表型存活中的作用。大多数实验在雄激素依赖性LNCaP细胞和雄激素非依赖性C4-2细胞中进行。这两种细胞系具有相同的遗传背景，因为C4-2系源自LNCaP系。建立葡萄糖剥夺（GD）以模拟这些细胞所遇到的能量应激。主要调查结果如下。首先，GD对AMPK的激活在C4-2细胞中比在LNCaP细胞中强得多，并且AMPK激活的稳健性与细胞活力有利地相关。第二，AMPK的反应是特定的能量缺乏，而不是氨基酸缺乏。GD对AMPK的激活是功能性的，如mTOR和mTOR下游底物的适当磷酸化变化所证明的。第三，通过化学抑制剂或显性失活AMPK阻断AMPK活化导致凋亡性细胞死亡增加。在其他雄激素非依赖性前列腺癌细胞系（包括CW 22 Rv 1 abd VCaP）中发现类似结果的观察结果进一步保证AMPK是前列腺癌细胞雄激素非依赖性道路上的促进剂。
Androgen-independent prostate cancer usually develops as a relapse following androgen ablation therapy. Removing androgen systemically causes vascular degeneration and nutrient depletion of the prostate tumor tissue. The fact that the malignancy later evolves to androgen-independence suggests that some cancer cells are able to survive the challenge of energy/nutrient deprivation. AMP-activated protein kinase (AMPK) is an important manager of energy stress. The present study was designed to investigate the role of AMPK in contributing to the survival of the androgen-independent phenotype. Most of the experiments were carried out in the androgen-dependent LNCaP cells and the androgen-independent C4-2 cells. These two cell lines have the same genetic background, since the C4-2 line is derived from the LNCaP line. Glucose deprivation (GD) was instituted to model energy stress encountered by these cells. The key findings are as follows. First, the activation of AMPK by GD was much stronger in C4-2 cells than in LNCaP cells, and the robustness of AMPK activation was correlated favorably with cell viability. Second, the response of AMPK was specific to energy deficiency rather than to amino acid deficiency. The activation of AMPK by GD was functional, as demonstrated by appropriate phosphorylation changes of mTOR and mTOR downstream substrates. Third, blocking AMPK activation by chemical inhibitor or dominant negative AMPK led to increased apoptotic cell death. The observation that similar results were found in other androgen-independent prostate cancer cell lines, including CW22Rv1 abd VCaP, provided further assurance that AMPK is a facilitator on the road to androgen-independence of prostate cancer cells.