PO.ET09.06 · 实验与分子治疗
丹参酮类似物通过抑制 MYC 和 E2F 通路诱导 ER 应激介导的前列腺癌细胞生长抑制
Tanshinone analog induces ER stress mediated growth suppression via inhibition of MYC and E2F pathways in prostate cancer cells
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摘要 Abstract
中文摘要
前列腺癌(PCa)是发达国家男性中最常见的恶性肿瘤,其发病率的上升与肥胖和代谢综合征患病率的升高密切相关。我们此前的研究表明,丹参酮类似物(TA)增强 ATF3 表达,抑制脂肪生成和脂质合成,并促进脂肪细胞棕色化。尽管天然丹参酮及其类似物均有报道可影响 PCa 细胞生长,但其潜在机制仍未完全阐明。本研究旨在探讨 TA 是否通过调节内质网(ER)应激/未折叠蛋白反应(UPR)和 E2F 家族相关通路来调控 PCa 细胞的生长。以雄激素依赖性 LNCaP 细胞和雄激素非依赖性 DU145 及 PC3 细胞作为 PCa 模型,我们考察了 TA 对细胞生长和相关信号通路的影响。经血细胞计数器计数确定,TA 处理以剂量依赖性方式显著减少了所有三种 PCa 细胞系的细胞数量。集落形成检测证实集落数量和直径均显著减少,表明具有强大的抗肿瘤活性。RNA 测序数据的基因集富集分析(GSEA)显示,TA 在 LNCaP 和 DU145 细胞中显著抑制了 MYC 和 E2F 靶点相关通路。相反,差异基因表达(DEG)富集分析显示 ER 应激相关通路上调,这通过 qPCR 和对 ER 应激标志物(包括 PERK、ATF6、IRE1α、ATF4 和 CHOP)的蛋白质印迹分析得到进一步验证。此外,TA 降低了 LNCaP 细胞中雄激素受体蛋白水平及其核转位。在体内,与对照组相比,TA 治疗(10 mg/kg,腹腔注射,每周两次,持续六周)显著降低了 DU145 异种移植免疫缺陷小鼠的肿瘤生长(2.30 ± 0.23 g 对比 3.53 ± 0.43 g;P < 0.05)。TA 治疗还降低了肺重量(相对于对照组)(0.21 ± 0.03 g 对比 0.36 ± 0.06 g;P < 0.05),表明有效抑制了肺转移。组织学分析进一步证实,TA 治疗组的原发性前列腺肿瘤和转移性肺肿瘤均小于对照组。此外,由于肝脏(ALT、AST)和肾脏(BUN、肌酐)生物标志物在 TA 治疗六周后保持不变,因此没有肝毒性或肾毒性的生化证据。总之,TA 通过激活 ER 应激和抑制 MYC 及 E2F 相关信号传导,在 PCa 中发挥多重抗肿瘤作用。这些发现凸显 TA 作为前列腺癌治疗的有前景的治疗候选药物。
查看英文原文 English abstract
Prostate cancer (PCa) is the most common malignancy among men in developed countries, and its increasing incidence is closely associated with the rising prevalence of obesity and metabolic syndrome. Our previous studies demonstrated that the Tanshinone analog (TA) enhances ATF3 expression, inhibits adipogenesis and lipogenesis, and promotes adipocyte browning. Although both native Tanshinones and their analogs have been reported to influence PCa cell growth, the underlying mechanisms remain incompletely understood. This study aimed to investigate whether TA regulates the growth of PCa cells through modulation of the endoplasmic reticulum (ER) stress/unfolded protein response (UPR) and E2F family-related pathways. Using androgen-dependent LNCaP cells and androgen-independent DU145 and PC3 cells as PCa models, we examined the effects of TA on cell growth and associated signaling pathways. TA treatment significantly reduced cell numbers in all three PCa cell lines in a dose-dependent manner, as determined by hemocytometer counting. Colony formation assays confirmed a marked decrease in both colony number and diameter, indicating strong anti-tumor activity. Gene Set Enrichment Analysis (GSEA) of RNA sequencing data revealed that TA markedly suppressed MYC- and E2F target-associated pathways in LNCaP and DU145 cells. In contrast, differential gene expression (DEG) enrichment analysis showed upregulation of ER stress-related pathways, which was further validated by qPCR and western blot analyses of ER stress markers including PERK, ATF6, IRE1alpha, ATF4, and CHOP. Additionally, TA reduced androgen receptor protein levels and its nuclear translocation in LNCaP cells. In vivo, TA treatment (10 mg/kg, i.p., twice weekly for six weeks) significantly reduced tumor growth in DU145 xenograft-bearing immunodeficient mice compared with controls (2.30 ± 0.23 g vs. 3.53 ± 0.43 g; P < 0.05). TA treatment also decreased lung weight relative to the control group (0.21 ± 0.03 g vs. 0.36 ± 0.06 g; P < 0.05), indicating effective inhibition of lung metastasis. Histological analysis further confirmed that both primary prostate tumors and metastatic lung tumors were smaller in the TA-treated group than in controls. Moreover, there was no biochemical evidence of hepatotoxicity or nephrotoxicity, as hepatic (ALT, AST) and renal (BUN, creatinine) biomarkers remained unchanged after six weeks of TA treatment. In conclusion, TA exerts multiple anti-tumor effects in PCa by activating ER stress and suppressing MYC- and E2F-related signaling. These findings highlight TA as a promising therapeutic candidate for prostate cancer treatment.
利益披露 Disclosure
C. Cheng, None..
H. Ku, None..
G. Cheng, None.