Department of Urology, The Sixth Affiliated Hospital of Sun Yat-Sen Univerisity, Guangzhou, China.
Department of Pharmacology, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.
Phytother Res. 2023 Jan;37(1):310-328. doi: 10.1002/ptr.7614. Epub 2022 Sep 9.
Prostate cancer (PCa) is the most common malignant tumor in males, which frequently develops into castration-resistant prostate cancer (CRPC) with limited therapies. Gambogenic acid (GNA), a flavonoids compound isolated from Gamboge, exhibits anti-tumor capacity in various cancers. Our results showed that GNA revealed not only antiproliferative and pro-apoptotic activities but also the induction of autophagy in PCa cells. In addition, autophagy inhibitor chloroquine enhanced the pro-apoptosis effect of GNA. Moreover, the activation of JNK pathway and the induction of apoptosis and autophagy triggered by GNA were attenuated by JNK inhibitor SP600125. We also found that GNA significantly promoted reactive oxygen species (ROS) generation and endoplasmic reticulum (ER) stress. Meanwhile, suppressing ER stress with 4-phenylbutyric acid (4-PBA) markedly blocked the activation of JNK pathway induced by GNA. Further research indicated that ROS scavenger N-acetyl-L-cysteine (NAC) effectively abrogated ER stress and JNK pathway activation induced by GNA. Furthermore, NAC and 4-PBA significantly reversed GNA-triggered apoptosis and autophagy. Finally, GNA remarkably suppressed prostate tumor growth with low toxicity in vivo. In conclusion, the present study revealed that GNA induced apoptosis and autophagy through ROS-mediated ER stress via JNK signaling pathway in PCa cells. Thus, GNA might be a promising therapeutic drug against PCa.
前列腺癌（PCa）是男性最常见的恶性肿瘤，经常发展为雄激素剥夺治疗抵抗性前列腺癌（CRPC），治疗方法有限。来自藤黄的一种黄酮类化合物 Gambogenic acid（GNA）在各种癌症中表现出抗肿瘤能力。我们的结果表明，GNA 不仅显示出抗增殖和促凋亡活性，而且还诱导 PCa 细胞自噬。此外，自噬抑制剂氯喹增强了 GNA 的促凋亡作用。此外，GNA 激活 JNK 途径并诱导细胞凋亡和自噬，这一作用被 JNK 抑制剂 SP600125 减弱。我们还发现，GNA 显著促进活性氧（ROS）的产生和内质网（ER）应激。同时，用 4-苯基丁酸（4-PBA）抑制 ER 应激明显阻断了 GNA 诱导的 JNK 途径的激活。进一步的研究表明，ROS 清除剂 N-乙酰-L-半胱氨酸（NAC）有效阻断了 GNA 诱导的 ER 应激和 JNK 途径的激活。此外，NAC 和 4-PBA 显著逆转了 GNA 诱导的细胞凋亡和自噬。最后，GNA 在体内显著抑制前列腺肿瘤生长，毒性低。总之，本研究表明，GNA 通过 ROS 介导的内质网应激通过 JNK 信号通路诱导 PCa 细胞凋亡和自噬。因此，GNA 可能是一种有前途的治疗前列腺癌的药物。
