Activated 3′,5′-cyclic AMP-dependent protein kinase is sufficient to induce neuroendocrine-like differentiation of the LNCaP prostate tumor cell line
Activated 3′,5′-cyclic AMP-dependent protein kinase is sufficient to induce neuroendocrine-like differentiation of the LNCaP prostate tumor cell line
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DOI：
10.1074/jbc.275.18.13812
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发表时间：
2000-05-05
影响因子：
4.8
通讯作者：
Parsons, SJ
中科院分区：
文献类型：
--
作者：
Cox, ME;Deeble, PD;Parsons, SJ
前列腺肿瘤内的神经内分泌（NE）分化被认为是疾病进展的一个促成因素。然而，前列腺NE细胞的细胞起源和分化的分子调控机制仍不清楚。前列腺肿瘤细胞系，LNCaP，可以可逆地获得许多NE的特性，以响应β-肾上腺素能受体激动剂和腺苷酸环化酶激活剂的治疗。在这项研究中，我们表明，这些治疗诱导蛋白激酶A（PKA）激活LNCaP细胞和异位表达的组成型激活形式的PKA催化亚基，CI α，结果在收购NE的特点，包括神经炎过程的延长，有丝分裂活动的停止，和生产的神经元特异性烯醇化酶。通过表达PKA调节亚基RI α的显性负突变体，毛喉素，肾上腺素和异丙肾上腺素依赖性NE分化的LNCaP细胞被显著抑制。这些结果表明，前列腺NE分化响应于这些药剂依赖于PKA活化，并且这种信号传导途径可以提供治疗晚期前列腺癌的治疗靶点。
Neuroendocrine (NE) differentiation within prostate tumors is proposed to be a contributing factor in disease progression. However, the cellular origin and molecular mechanism controlling differentiation of prostatic NE cells are unresolved. The prostate tumor cell line, LNCaP, can reversibly acquire many NE characteristics in response to treatment with beta-adrenergic receptor agonists and activators of adenylate cyclase. In this study, we demonstrate that these treatments induce protein kinase A (PKA) activation in LNCaP cells and that ectopic expression of a constitutively activated form of the PKA catalytic subunit, CI alpha, results in acquisition of NE characteristics, including the extension of neuritic processes, cessation of mitotic activity, and production of neuron-specific enolase. Forskolin-, epinephrine-, and isoproterenol-dependent NE differentiation of LNCaP cells was significantly inhibited by expressing a dominant negative mutant of the PKA regulatory subunit, RI alpha, These results demonstrate that prostatic NE differentiation in response to these agents depends on PKA activation, and this signaling pathway may provide a therapeutic target for treating advanced forms of prostate cancer.