Graduate Institute of Natural Products, Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
Department of Pharmacognosy, Interdisciplinary Excellence Centre, University of Szeged, Eötvös u. 6, H-6720 Szeged, Hungary.
Int J Mol Sci. 2020 Oct 14;21(20):7579. doi: 10.3390/ijms21207579.
Prostratin, a non-tumor promoting 12-deoxyphorbol ester, has been reported as a protein kinase C (PKC) activator and is shown to have anti-proliferative activity in certain cancer cell types. Here we show that GRC-2, a prostratin analogue isolated from , is ten-fold more potent than prostratin for inhibiting the growth of human non-small cell lung cancer (NSCLC) A549 cells. Flow cytometry assay revealed that GRC-2 and prostratin inhibited cell cycle progression at the G2/M phase and induced apoptosis. The cytotoxic effect of GRC-2 and prostratin was accompanied by activation and nuclear translocation of PKC-δ and PKD as well as hyperactivation of extracellular signal-related kinase (ERK). Knockdown of either PKC-δ, PKD or ERK significantly protected A549 cancer cells from GRC-2- and prostratin-induced growth arrest as well as apoptosis. Taken together, our results have shown that prostratin and a more potent analogue GRC-2 reduce cell viability in NSCLC A549 cells, at least in part, through activation of the PKC-δ/PKD/ERK pathway, suggesting the potential of prostratin and GRC-2 as anticancer agents.
普拉司他汀是一种非肿瘤促进的 12-去氧佛波醇酯，已被报道为蛋白激酶 C（PKC）激活剂，并显示在某些癌细胞类型中具有抗增殖活性。在这里，我们表明，从 中分离出的普拉司他汀类似物 GRC-2 比普拉司他汀抑制人非小细胞肺癌（NSCLC）A549 细胞生长的效力高十倍。流式细胞术分析显示，GRC-2 和普拉司他汀抑制细胞周期在 G2/M 期进展，并诱导细胞凋亡。GRC-2 和普拉司他汀的细胞毒性作用伴随着 PKC-δ 和 PKD 的激活和核转位以及细胞外信号相关激酶（ERK）的超活化。PKC-δ、PKD 或 ERK 的敲低显著保护 A549 癌细胞免受 GRC-2 和普拉司他汀诱导的生长停滞和细胞凋亡。总之，我们的结果表明，普拉司他汀和一种更有效的类似物 GRC-2 通过激活 PKC-δ/PKD/ERK 通路降低 NSCLC A549 细胞的活力，至少部分是通过激活 PKC-δ/PKD/ERK 通路，表明普拉司他汀和 GRC-2 作为抗癌药物的潜力。
