Direct estradiol and diethylstilbestrol actions on early- versus late-stage prostate cancer cells.
Direct estradiol and diethylstilbestrol actions on early- versus late-stage prostate cancer cells.
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DOI：
10.1002/pros.22875
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发表时间：
2014-12
期刊：
影响因子：
2.8
通讯作者：
Watson, Cheryl S.
中科院分区：
文献类型：
--
作者：
Koong, Luke Y.;Watson, Cheryl S.
己烯雌酚（DES）和其他药物雌激素在≥μM浓度下已用于治疗晚期前列腺肿瘤，成功主要归因于间接的下丘脑-垂体-睾丸轴控制机制。然而，雌激素也直接影响肿瘤细胞，尽管所涉及的机制还不清楚。LAPC-4（雄激素依赖性）和PC-3（雄激素非依赖性）细胞活力测定后，雌二醇（E2）或DES处理在很宽的浓度范围。然后，我们在0.1 nM E2和1μM DES最适条件下研究了多种快速信号传导机制，包括：丝裂原活化蛋白激酶、细胞周期蛋白和半胱天冬酶3的活化（磷酸化）、坏死性凋亡和活性氧（ROS）水平。LAPC-4细胞比PC-3细胞更敏感。强大的和持续的细胞外调节激酶激活与E2，而不是DES，与ROS的产生和细胞死亡。c-Jun N-末端激酶仅在E2处理的PC-3细胞中激活，并且与caspase 3介导的凋亡无关;不涉及坏死性凋亡。细胞周期抑制蛋白p16 INK 4A在两种细胞系中均被E2和DES磷酸化，但程度不同。在这两种细胞类型中，两种雌激素激活p38激酶，随后磷酸化细胞周期蛋白D1，标记它的降解，除了在DES处理的PC-3细胞。细胞周期蛋白D1状态与细胞周期中断密切相关，是细胞数量减少的原因，尽管其他机制也有贡献。低至0.1 nM的E2有效地引发了这些机制，它的使用可以显着改善早期和晚期前列腺癌患者的结局，同时避免高剂量DES治疗的副作用。
Diethylstilbestrol (DES) and other pharmaceutical estrogens have been used at ≥μM concentrations to treat advanced prostate tumors, with successes primarily attributed to indirect hypothalamic-pituitary-testicular axis control mechanisms. However, estrogens also directly affect tumor cells, though the mechanisms involved are not well understood. LAPC-4 (androgen-dependent) and PC-3 (androgen-independent) cell viability was measured after estradiol (E2) or DES treatment across wide concentration ranges. We then examined multiple rapid signaling mechanisms at 0.1 nM E2 and 1μM DES optima including levels of: activation (phosphorylation) for mitogen-activated protein kinases, cell-cycle proteins, and caspase 3, necroptosis, and reactive oxygen species (ROS). LAPC-4 cells were more responsive than PC-3 cells. Robust and sustained extracellular-regulated kinase activation with E2, but not DES, correlated with ROS generation and cell death. c-Jun N-terminal kinase was only activated in E2-treated PC-3 cells and was not correlated with caspase 3-mediated apoptosis; necroptosis was not involved. The cell-cycle inhibitor protein p16INK4A was phosphorylated in both cell lines by both E2 and DES, but to differing extents. In both cell types, both estrogens activated p38 kinase, which subsequently phosphorylated cyclin D1, tagging it for degradation, except in DES-treated PC-3 cells. Cyclin D1 status correlated most closely with disrupted cell cycling as a cause of reduced cell numbers, though other mechanisms also contributed. As low as 0.1 nM E2 effectively elicited these mechanisms, and its use could dramatically improve outcomes for both early- and late-stage prostate cancer patients, while avoiding the side effects of high-dose DES treatment.
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影响因子：
14.8
作者：
Degterev, A;Huang, ZH;Yuan, JY
通讯作者：
Yuan, JY
影响因子：
2.7
作者：
Bulayeva, NN;Gametchu, B;Watson, CS
通讯作者：
Watson, CS
细胞周期蛋白D1降解的调节：在癌症发展中的作用和治疗发明的潜力。
影响因子：
37.3
作者：
Alao, John P.
通讯作者：
Alao, John P.
影响因子：
--
作者：
Jeng YJ;Kochukov MY;Watson CS
通讯作者：
Watson CS
影响因子：
12.4
作者：
Jouan-Lanhouet, S.;Arshad, M. I.;Dimanche-Boitrel, M-T
通讯作者：
Dimanche-Boitrel, M-T