Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Cell Signal. 2011 Sep;23(9):1466-72. doi: 10.1016/j.cellsig.2011.04.008. Epub 2011 Apr 28.
The present study was designed to investigate (i) the role of AMPK activation in inducing autophagy in androgen-dependent prostate cancer cells subjected to androgen deprivation and hypoxia, and (ii) whether autophagy offers a survival advantage under these harsh conditions. Low androgen and low oxygen are two co-existing conditions frequently found in prostate cancer tissue following surgical or medical castration. In LNCaP cells, androgen deprivation and hypoxia together boosted AMPK activation to a higher level than that seen with either condition alone. The augmented AMPK response was associated with improved viability and the induction of autophagy. These observations suggest that a threshold of AMPK activity has to be attained in order to trigger autophagy, since neither androgen deprivation nor hypoxia by itself was capable of pushing AMPK activity past that threshold. Beclin-1 was identified as a potential downstream target of AMPK in turning on the autophagic cascade. If autophagy was blocked by chemical inhibition or RNA interference of key regulators, e.g., AMPK or beclin-1, more cells would die by apoptosis. The occurrence of autophagy is thus a survival mechanism for androgen-dependent prostate cancer cells to escape from an androgen-deprived and hypoxic subsistence.
(i) 在雄激素剥夺和缺氧条件下，AMPK 激活在诱导雄激素依赖性前列腺癌细胞自噬中的作用；(ii) 在这些恶劣条件下，自噬是否提供生存优势。雄激素水平低和氧气含量低是前列腺癌组织在手术或药物去势后经常出现的两种共存条件。在 LNCaP 细胞中，雄激素剥夺和缺氧共同促进 AMPK 激活至比单一条件更高的水平。增强的 AMPK 反应与提高的细胞活力和自噬的诱导有关。这些观察结果表明，为了触发自噬，必须达到 AMPK 活性的阈值，因为雄激素剥夺或缺氧本身都不能将 AMPK 活性推过该阈值。Beclin-1 被鉴定为 AMPK 的一个潜在下游靶点，可开启自噬级联反应。如果通过化学抑制或关键调节剂（如 AMPK 或 beclin-1）的 RNA 干扰阻断自噬，更多的细胞将通过凋亡死亡。因此，自噬的发生是雄激素依赖性前列腺癌细胞逃避雄激素剥夺和缺氧生存的一种生存机制。
