Prostate cancer (PCa) has different molecular features along progression, including androgen profile, which is associated to therapy inefficiency leading to more aggressive phenotype. Docosahexaenoic acid (DHA) has antiproliferative and pro-apoptotic properties in different cancers associated to cell metabolism modulation. The latter is of particular interest since metabolic reprogramming is one of PCa hallmarks, but is not clear how this occurs among disease progression. Therefore, we evaluated DHA antiproliferative potential in distinct androgenic backgrounds associated to metabolism modulation and androgen-regulated genes. For this purpose, pre-malignant PNT1A and tumor AR-positive 22rv1, and AR-negative PC3 cells were incubated with DHA at 100 μM–48 h. DHA reduced at least 26% cell number for all lineages due to S-phase decrease in AR-positive and G2/M arrest in AR-negative. Mitochondrial metabolic rate decreased in PNT1A (~38%) and increased in tumor cells (at least 40%). This was associated with ROS overproduction (1.6-fold PNT1A; 2.1 22rv1; 2.2 PC3), lipid accumulation (3-fold PNT1A; 1.8 22rv1; 3.6 PC3) and mitochondria damage in all cell lines. AKT, AMPK and PTEN were not activated in any cell line, but p-ERK1/2 increased (1.5-fold) in PNT1A. Expression of androgen-regulated and nuclear receptors genes showed that DHA affected them in a distinct pattern in each cell line, but most converged to metabolism regulation, response to hormones, lipids and stress. In conclusion, regardless of androgenic or PTEN background DHA exerted antiproliferative effect associated to cell cycle impairment, lipid deregulation and oxidative stress, but differentially regulated gene expression probably due to distinct molecular features of each pathologic stage.

前列腺癌（PCa）沿病程具有不同的分子特征，包括雄激素谱，这与治疗效率低下相关，导致更具攻击性的表型。二十二碳六烯酸（DHA）在与细胞代谢调节相关的不同癌症中具有抗增殖和促凋亡特性。后者特别令人感兴趣，因为代谢重编程是PCa的标志之一，但尚不清楚这在疾病进展中如何发生。因此，我们在与代谢调节和雄激素调节基因相关的不同雄激素背景下评估了DHA的抗增殖潜力。为此，将恶性前PNT1A和肿瘤AR阳性22rv1和AR阴性PC3细胞与DHA在100 μM–48 h孵育。由于AR阳性的S期减少和AR阴性的G2 / M停滞，DHA减少了所有谱系的至少26％的细胞数。PNT1A的线粒体代谢率下降（约38％），而肿瘤细胞的线粒体代谢率上升（至少40％）。这与所有细胞系中的ROS过度产生（1.6倍PNT1A; 2.1 22rv1; 2.2 PC3），脂质蓄积（3倍PNT1A; 1.8 22rv1; 3.6 PC3）和线粒体损伤有关。AKT，AMPK和PTEN在任何细胞系中均未激活，但PNT1A中的p-ERK1 / 2增加（1.5倍）。雄激素调节和核受体基因的表达表明，DHA在每种细胞系中均以独特的方式影响它们，但大多数都集中于代谢调节，对激素，脂质和压力的反应。总之，不管DHA的作用是雄激素还是PTEN，都与细胞周期受损有关，具有抗增殖作用，