Hairston Dontrel W Spencer, Sridharan-Weaver Shamira, Gandhi Abheek, Batra Neelu, Durbin-Johnson Blythe P, Dall'Era Marc A, Ghosh Paramita M
Veterans Affairs-Northern California Health System, Mather, CA 95655, USA.
Department of Urologic Surgery, School of Medicine, University of California Davis, Sacramento, CA 95718, USA.
Molecules. 2025 Aug 8;30(16):3316. doi: 10.3390/molecules30163316.
However, in many cases, patients experience biochemical recurrence (BCR), heralded by rising prostate specific antigen (PSA) levels in the serum. Our goal was to identify metabolic pathways that are disrupted in BCR to determine potential targets of therapy. We conducted metabolomic analysis in prostate tissue from the tumors of 74 patients who underwent prostatectomy as treatment for localized PCa and correlated levels of metabolites with clinical and non-clinical factors. Cholesterol and triglycerides were upregulated in Hispanic vs. non-Hispanic and in obese vs. non-obese individuals, respectively. Both lipids and non-lipids were altered with increasing Gleason grades and clinical stages. High post-RP PSA (>0.1 ng/mL) indicated recurrence ( = 0.0094) and correlated with alterations in 141 metabolites including 114 lipids and 26 non-lipid molecules. The largest increase with high post-RP PSA was in 2-hydroxyglutaric acid (2-HG), a product of the tricarboxylic acid (TCA) cycle, that had previously been established as an oncometabolite in other cancers. 2-HG was highly selective and specific for high post-RP PSA (AUC = 0.8526; = 0.0002) while Kaplan-Meier curves indicated that among patients who recurred, high 2-HG in the tumor reduced time-to-recurrence from 84 months (for those with low 2-HG) to 38 months (for those with high 2-HG). The addition of D2HG, an enantiomer of 2-HG, increased the growth rate of LNCaP and C4 cells, and also increased Akt and ERK phosphorylation. 2-HG is upregulated in PCa tumors from patients who experience high post-RP PSA indicative of recurrence. Future studies may target this metabolite to prevent recurrent disease.
然而，在许多情况下，患者会经历生化复发（BCR），血清中前列腺特异性抗原（PSA）水平升高预示着这一情况。我们的目标是确定在生化复发中被破坏的代谢途径，以确定潜在的治疗靶点。我们对74例接受前列腺切除术治疗局限性前列腺癌（PCa）患者的肿瘤组织进行了代谢组学分析，并将代谢物水平与临床和非临床因素相关联。胆固醇和甘油三酯分别在西班牙裔与非西班牙裔个体以及肥胖与非肥胖个体中上调。脂质和非脂质均随 Gleason 分级和临床分期的增加而改变。前列腺切除术后高 PSA（>0.1 ng/mL）表明复发（P = 0.0094），并与141种代谢物的改变相关，包括114种脂质和26种非脂质分子。前列腺切除术后高 PSA 导致最大增幅的是2-羟基戊二酸（2-HG），它是三羧酸（TCA）循环的产物，此前已被确定为其他癌症中的一种肿瘤代谢物。2-HG对前列腺切除术后高 PSA 具有高度选择性和特异性（AUC = 0.8526；P = 0.0002），而 Kaplan-Meier 曲线表明，在复发患者中，肿瘤中高浓度的2-HG 将复发时间从84个月（2-HG 浓度低的患者）缩短至38个月（2-HG 浓度高的患者）。添加2-HG的对映体D2HG可提高LNCaP和C4细胞的生长速率，还可增加Akt和ERK磷酸化。在经历前列腺切除术后高 PSA 预示复发的患者的PCa肿瘤中，2-HG上调。未来的研究可能针对这种代谢物来预防疾病复发。
