Department of Urology, The Affiliated Hospital of Jiaxing University, Jiaxing, China.
College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, China.
Oxid Med Cell Longev. 2022 Aug 4;2022:9325973. doi: 10.1155/2022/9325973. eCollection 2022.
Rosin derivatives such as dehydroabietic acid and dehydroabietic amine belonging to diterpenoids have similar structure with androgen that inhibited the occurrence and development of prostate cancer. In this study, the effects and possible mechanism of the rosin derivative IDOAMP on prostate cancer were investigated. Our results showed that IDOAMP effectively inhibited cell viabilities of LNCaP, PC3, and DU145 prostate cells. After the treatment with IDOAMP, the levels of cleaved-PARP, LC3BII/I, and HMGB1 were increased, whereas the expression of GPX4 was decreased. Interestingly, cell viability was reversed by the supplements of necrostatin-1 and necrosulfonamide. Meanwhile, the IDOAMP downregulated the expression of human Aurora kinase A that was overexpressed in prostate cancer. In addition, co-IP results showed that IDOAMP inhibited the binding of Aurora kinase A to the receptor-interacting serine/threonine kinase 1 (RIPK1) and RIPK3. However, the binding of RIPK1 to FADD, RIPK3, or MLKL was significantly promoted. Further studies showed that the phosphorylation levels of RIPK1, RIPK, and MLKL were increased in a concentration-dependent manner. In in vivo model, IDOAMP reduced the tumor volumes and weights. In conclusion, IDOAMP directly inhibited Aurora kinase A and promoted the RIPK1/RIPK3/MLKL necrosome activation to inhibit the prostate cancer.
松香衍生物，如去氢枞酸和去氢枞胺，属于二萜类化合物，与雄激素具有相似的结构，可抑制前列腺癌的发生和发展。在本研究中，研究了松香衍生物 IDOAMP 对前列腺癌的作用及可能机制。结果表明，IDOAMP 能有效抑制 LNCaP、PC3 和 DU145 前列腺细胞的活力。用 IDOAMP 处理后，cleaved-PARP、LC3BII/I 和 HMGB1 的水平升高，而 GPX4 的表达降低。有趣的是，补充 necrostatin-1 和 necrosulfonamide 可逆转细胞活力。同时，IDOAMP 下调了在前列腺癌中过表达的人 Aurora 激酶 A 的表达。此外，Co-IP 结果表明，IDOAMP 抑制了 Aurora 激酶 A 与受体相互作用丝氨酸/苏氨酸激酶 1（RIPK1）和 RIPK3 的结合。然而，RIPK1 与 FADD、RIPK3 或 MLKL 的结合显著增加。进一步的研究表明，RIPK1、RIPK 和 MLKL 的磷酸化水平呈浓度依赖性增加。在体内模型中，IDOAMP 降低了肿瘤体积和重量。综上所述，IDOAMP 直接抑制 Aurora 激酶 A，并促进 RIPK1/RIPK3/MLKL 坏死小体的激活，从而抑制前列腺癌。
