Cancer Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.
Department of Pharmacy, Sahmyook University, Seoul, Korea.
Prostate. 2023 May;83(6):534-546. doi: 10.1002/pros.24482. Epub 2023 Jan 3.
We have shown that decursin, a coumarin compound, induces cell cycle arrest and apoptosis in human prostate cancer cells (PCa); however, its molecular mechanisms are largely unexplored. We studied the mechanisms associated with its anticancer activity in advanced human prostate carcinoma cells. We found that decursin inhibited epidermal growth factor receptor (EGFR) signaling by inhibiting its activating phosphorylation at tyrosine 1068 residue in DU145 and 22Rv1 cells. This inhibition of EGFR was associated with the downregulation of ERK1/2 phosphorylation. Both EGFR and ERK1/2 are known to be deregulated/activated in many human malignancies. Consistent with our earlier study, decursin (25-100 µM) treatment for 24-72 h inhibited DU145 cell proliferation by 49%-87% (p < 0.001) which was associated with strong G1 phase arrest and cell death. It also decreased (p < 0.001) the number of surviving colonies. Decursin moderately increased the expression of Rb-related proteins p107 and p130 but decreased the levels of E2F family transcription factors including E2F-3, E2F-4 and E2F-5. Further, decursin strongly inhibited the growth of androgen-dependent prostate carcinoma 22Rv1 cells from 61% to 79% (p < 0.001) and arrested these cells at G1 phase via induction of cyclin-dependent kinase inhibitor p27/Kip1 and downregulation of CDK2 and CDK4 protein expression. Additionally, EGFR inhibitor erlotinib- and EGF ligand-modulated EGFR activation validated EGFR signaling as a target of decursin-mediated cell growth inhibition and cytotoxicity. Decursin decreased EGF ligand-induced phosphorylation of EGFR (Y-1068) as well as activation of its downstream mediator, ERK1/2. Furthermore, inhibitory targeting of EGFR-ERK1/2 axis by combinatorial treatment of decursin and erlotinib further sensitized DU145 cells for the decursin-induced growth inhibition and cell death. Overall, these findings strongly suggest that anticancer efficacy of decursin against human PCa involves inhibitory targeting of EGFR-ERK1/2 signaling axis, a pathway constitutively active in advanced PCa.
我们已经证明，一种香豆素化合物蛇床定能够诱导人前列腺癌细胞（PCa）的细胞周期停滞和凋亡；然而，其分子机制在很大程度上仍未得到探索。我们研究了其在晚期人前列腺癌细胞中抗癌活性相关的机制。我们发现蛇床定通过抑制 DU145 和 22Rv1 细胞中酪氨酸 1068 残基的激活磷酸化来抑制表皮生长因子受体（EGFR）信号。这种 EGFR 的抑制与 ERK1/2 磷酸化的下调有关。众所周知，EGFR 和 ERK1/2 在许多人类恶性肿瘤中都失调/激活。与我们之前的研究一致，蛇床定（25-100 μM）处理 24-72 小时可使 DU145 细胞增殖抑制 49%-87%（p<0.001），这与强烈的 G1 期阻滞和细胞死亡有关。它还降低了（p<0.001）存活集落的数量。蛇床定适度增加了 Rb 相关蛋白 p107 和 p130 的表达，但降低了包括 E2F-3、E2F-4 和 E2F-5 在内的 E2F 家族转录因子的水平。此外，蛇床定强烈抑制雄激素依赖性前列腺癌 22Rv1 细胞的生长，抑制率为 61%-79%（p<0.001），通过诱导细胞周期蛋白依赖性激酶抑制剂 p27/Kip1 和下调 CDK2 和 CDK4 蛋白表达，将这些细胞阻滞在 G1 期。此外，表皮生长因子受体抑制剂厄洛替尼和表皮生长因子配体调节表皮生长因子受体（EGFR）的激活，验证了 EGFR 信号是蛇床定介导的细胞生长抑制和细胞毒性的靶点。蛇床定降低了表皮生长因子配体诱导的 EGFR（Y-1068）磷酸化以及其下游介质 ERK1/2 的激活。此外，蛇床定和厄洛替尼联合治疗对 EGFR-ERK1/2 轴的抑制作用进一步增强了 DU145 细胞对蛇床定诱导的生长抑制和细胞死亡的敏感性。总的来说，这些发现强烈表明，蛇床定对人前列腺癌的抗癌疗效涉及对 EGFR-ERK1/2 信号轴的抑制作用，该通路在晚期前列腺癌中持续激活。
