College of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan 609-735, Republic of Korea.
Int J Oncol. 2014 Mar;44(3):905-11. doi: 10.3892/ijo.2014.2257. Epub 2014 Jan 10.
Previously, we reported on the anticancer effect of the diastereoisomeric compound MHY-449, a novel dihydro-benzofuro[4,5-b][1,8] naphthyridin-6-one derivative, in HCT116 human colon cancer cells. In the current study, we investigated whether MHY-449 has anticancer effect in prostate cancer cells, and if so, what the molecular mechanisms are. We examined the growth inhibitory effect of MHY-449 on p53 wild‑type (p53-wt) LNCaP (androgen‑dependent) and p53-null PC3 (androgen-independent) prostate cancer cells. MHY-449 treatment in androgen-independent and p53-null PC3 cells resulted in inhibition of cell growth and induction of apoptosis in a concentration-dependent manner. However, MHY-449 did not show any significant effects on the growth inhibition and apoptotic cell death in androgen-dependent and p53-wt LNCaP cells. Therefore, we used PC3 cells for further studies. The induction of apoptosis in PC3 cells was observed by decreased viability, DNA fragmentation, cleavage of poly (ADP-ribose) polymerase, activations of caspase-3, -8 and -9, and alteration in the ratio of Bax/Bcl-2 protein expression. In addition, MHY-449 induced increase of late apoptosis and sub-G1 DNA which were observed by flow cytometry analysis. Furthermore, MHY-449 reduced the phosphorylation of Akt and FoxO1 and induced the translocation of FoxO1 from cytoplasm to nucleus as shown by western blot analysis. MHY-449 treatment activated extracellular signal-regulated kinase (ERK) signaling in a concentration-dependent manner. MHY-449-induced apoptosis was partially prevented by pretreatment with the ERK inhibitor PD98059 suggesting involvement of ERK in the MHY-449-induced apoptosis. Taken together, these findings suggest that MHY-449 induces apoptosis via downregulation of the Akt/FoxO1 and activation of ERK in androgen-independent, p53-null and PTEN-negative PC3 human prostate cancer cells.
先前，我们报道了新型二氢苯并呋喃[4,5-b][1,8]萘啶-6-酮衍生物 MHY-449 对 HCT116 人结肠癌细胞的抗癌作用。在本研究中，我们研究了 MHY-449 是否对前列腺癌细胞具有抗癌作用，如果有，其分子机制是什么。我们检测了 MHY-449 对 p53 野生型（p53-wt）LNCaP（雄激素依赖性）和 p53 缺失型 PC3（雄激素非依赖性）前列腺癌细胞生长抑制作用。MHY-449 处理雄激素非依赖性和 p53 缺失型 PC3 细胞，可浓度依赖性地抑制细胞生长并诱导细胞凋亡。然而，MHY-449 对雄激素依赖性和 p53-wt LNCaP 细胞的生长抑制和凋亡细胞死亡没有任何显著影响。因此，我们使用 PC3 细胞进行了进一步的研究。在 PC3 细胞中，通过降低细胞活力、DNA 片段化、多聚（ADP-核糖）聚合酶的切割、caspase-3、-8 和 -9 的激活以及 Bax/Bcl-2 蛋白表达比值的改变，观察到细胞凋亡的诱导。此外，通过流式细胞术分析观察到 MHY-449 诱导晚期凋亡和亚 G1 DNA 的增加。此外，MHY-449 降低了 Akt 和 FoxO1 的磷酸化，并通过 Western blot 分析诱导 FoxO1 从细胞质转位到细胞核。MHY-449 以浓度依赖性方式激活细胞外信号调节激酶（ERK）信号。ERK 抑制剂 PD98059 预处理可部分阻止 MHY-449 诱导的细胞凋亡，提示 ERK 参与了 MHY-449 诱导的细胞凋亡。总之，这些发现表明 MHY-449 通过下调 Akt/FoxO1 和激活雄激素非依赖性、p53 缺失型和 PTEN 阴性 PC3 人前列腺癌细胞中的 ERK 诱导细胞凋亡。
Zotero 插件