通过单羧酸转运蛋白 1 抑制剂增强前列腺癌细胞中的雄激素剥夺疗法的抗癌效果。

Enhancing the anticancer effect of androgen deprivation therapy by monocarboxylate transporter 1 inhibitor in prostate cancer cells.

机构信息

Division of Life Sciences, College of Life Science and Bioengineering, Incheon National University, Incheon, South Korea.

Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, South Korea.

出版信息

Prostate. 2024 Jun;84(9):814-822. doi: 10.1002/pros.24700. Epub 2024 Apr 1.

DOI:10.1002/pros.24700

PMID:38558458

Abstract

BACKGROUND

Tumor initiation and progression necessitate a metabolic shift in cancer cells. Consequently, the progression of prostate cancer (PCa), a leading cause of cancer-related deaths in males globally, involves a shift from lipogenic to glycolytic metabolism. Androgen deprivation therapy (ADT) serves as the standard treatment for advanced-stage PCa. However, despite initial patient responses, castrate resistance emerges ultimately, necessitating novel therapeutic approaches. Therefore, in this study, we aimed to investigate the role of monocarboxylate transporters (MCTs) in PCa post-ADT and evaluate their potential as therapeutic targets.

METHODS

PCa cells (LNCaP and C4-2 cell line), which has high prostate-specific membrane antigen (PSMA) and androgen receptor (AR) expression among PCa cell lines, was used in this study. We assessed the expression of MCT1 in PCa cells subjected to ADT using charcoal-stripped bovine serum (CSS)-containing medium or enzalutamide (ENZ). Furthermore, we evaluated the synergistic anticancer effects of combined treatment with ENZ and SR13800, an MCT1 inhibitor.

RESULTS

Short-term ADT led to a significant upregulation in folate hydrolase 1 (FOLH1) and solute carrier family 16 member 1 (SLC16A1) gene levels, with elevated PSMA and MCT1 protein levels. Long-term ADT induced notable changes in cell morphology with further upregulation of FOLH1/PSMA and SLC16A1/MCT1 levels. Treatment with ENZ, a nonsteroidal anti-androgen, also increased PSMA and MCT1 expression. However, combined therapy with ENZ and SR13800 led to reduced PSMA level, decreased cell viability, and suppressed expression of cancer stem cell markers and migration indicators. Additionally, analysis of human PCa tissues revealed a positive correlation between PSMA and MCT1 expression in tumor regions.

CONCLUSIONS

Our results demonstrate that ADT led to a significant upregulation in MCT1 levels. However, the combination of ENZ and SR13800 demonstrated a promising synergistic anticancer effect, highlighting a potential therapeutic significance for patients with PCa undergoing ADT.

摘要

背景

肿瘤的发生和发展需要癌细胞发生代谢转变。因此，前列腺癌（PCa）的进展，这种疾病是全球男性癌症相关死亡的主要原因，涉及从脂肪生成到糖酵解代谢的转变。雄激素剥夺疗法（ADT）是晚期 PCa 的标准治疗方法。然而，尽管患者最初有反应，但最终会出现去势抵抗，需要新的治疗方法。因此，在这项研究中，我们旨在研究单羧酸转运蛋白（MCT）在 ADT 后 PCa 中的作用，并评估其作为治疗靶点的潜力。

方法

本研究使用前列腺特异性膜抗原（PSMA）和雄激素受体（AR）在 PCa 细胞系中表达较高的 PCa 细胞（LNCaP 和 C4-2 细胞系）。我们使用含去垢剂牛血清（CSS）的培养基或恩扎卢胺（ENZ）评估 ADT 后 MCT1 在 PCa 细胞中的表达。此外，我们评估了联合使用 ENZ 和 MCT1 抑制剂 SR13800 的协同抗癌作用。

结果

短期 ADT 导致叶酸水解酶 1（FOLH1）和溶质载体家族 16 成员 1（SLC16A1）基因水平显著上调，PSMA 和 MCT1 蛋白水平升高。长期 ADT 诱导细胞形态发生显著变化，FOLH1/PSMA 和 SLC16A1/MCT1 水平进一步上调。非甾体类抗雄激素 ENZ 的治疗也增加了 PSMA 和 MCT1 的表达。然而，ENZ 和 SR13800 的联合治疗导致 PSMA 水平降低、细胞活力降低、抑制癌症干细胞标志物和迁移指标的表达。此外，对人类 PCa 组织的分析表明，肿瘤区域的 PSMA 和 MCT1 表达呈正相关。