The Kinghorn Cancer Centre, Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia.
Br J Cancer. 2013 Dec 10;109(12):3034-41. doi: 10.1038/bjc.2013.693. Epub 2013 Oct 31.
Persin is a plant toxin that displays synergistic cytotoxicity with tamoxifen in human breast cancer cell lines. Here, we examined the ability of persin to circumvent tamoxifen resistance and delineated the intracellular signalling pathways involved.
The induction of apoptosis in tamoxifen-resistant and -sensitive breast cancer cells was measured by flow cytometry following treatment with persin±tamoxifen. Markers of endoplasmic reticulum stress (ERS) were analysed following treatment, and their causal role in mediating persin-induced apoptosis was determined using chemical inhibitors and RNA interference.
Cells that were resistant to an apoptotic concentration of tamoxifen maintained an apoptotic response to persin. Persin-induced apoptosis was associated with an increase in markers of ERS, that is, CHOP expression and XBP-1 splicing and was decreased by CHOP siRNA. The CASP-4 inhibitor Z-YVAD-FMK markedly inhibited persin-induced apoptosis in both tamoxifen-sensitive and -resistant cells.
The cytotoxic effects of persin are CASP-4 dependent and mediated by CHOP-dependent and -independent ERS signalling cascades. Increased ERS signalling contributes to persin-induced reversal of tamoxifen resistance.
展青霉素是一种植物毒素，它在人乳腺癌细胞系中与他莫昔芬表现出协同细胞毒性。在这里，我们研究了展青霉素规避他莫昔芬耐药性的能力，并阐明了涉及的细胞内信号通路。
用展青霉素处理后，通过流式细胞术测量他莫昔芬耐药和敏感的乳腺癌细胞中细胞凋亡的诱导。处理后分析内质网应激（ERS）标志物，并使用化学抑制剂和 RNA 干扰确定其在介导展青霉素诱导的细胞凋亡中的因果作用。
对凋亡浓度的他莫昔芬耐药的细胞对展青霉素保持凋亡反应。展青霉素诱导的细胞凋亡与 ERS 标志物（即 CHOP 表达和 XBP-1 剪接）的增加有关，而 CHOP siRNA 则降低了其表达。CASP-4 抑制剂 Z-YVAD-FMK 显著抑制了他莫昔芬敏感和耐药细胞中展青霉素诱导的细胞凋亡。
展青霉素的细胞毒性作用依赖于 CASP-4，并通过 CHOP 依赖性和非依赖性 ERS 信号通路介导。增加的 ERS 信号有助于展青霉素诱导的他莫昔芬耐药性逆转。
