Strigolactone analogs induce apoptosis through activation of p38 and the stress response pathway in cancer cell lines and in conditionally reprogrammed primary prostate cancer cells

Strigolactones are a novel class of plant hormones produced in roots and regulate shoot and root development. We have previously shown that synthetic strigolactone analogues potently inhibit growth of breast cancer cells and breast cancer stem cells. Here we show that strigolactone analogues inhibit the growth and survival of an array of cancer-derived cell lines representing solid and non-solid cancer cells including: prostate, colon, lung, melanoma, osteosarcoma and leukemic cell lines, while normal cells were minimally affected. Furthermore, we tested the response of patient-matched conditionally reprogrammed normal and prostate cancer cells. The tumor cells exhibited significantly higher sensitivity to the two most potent SL analogues with increased apoptosis compared to their normal counterpart cells. Treatment of cancer cells with strigolactone analogues was hallmarked by increased expression and activity of genes involved in stress signaling, cell cycle arrest and apoptosis. All five strigolactone analogues induced G2/M cell cycle arrest, accompanied with a decrease in the expression level of cyclin B1. Apoptosis was marked by increased percentages of cells in the sub-G1 fraction and was confirmed by Annexin V staining. In conditionally reprogramed matched tumor and normal prostate cells, the cleavage of PARP1 confirmed the specific increase in apoptosis of tumor cells. In summary, Strigolactone analogues are promising candidates for anticancer therapy by their ability to specifically induce cell cycle arrest, cellular stress and apoptosis in tumor cells with minimal effects on growth and survival of normal cells. There are duplicate samples for each condition. U2OS cells were treated with 2 different strigolactone analogues: ST362 or MEB55 at the concentration of 5 ppm for either 6 hr or 24 hr.Control samples were those treated with vehicle only .

独脚金内酯（Strigolactones）是一类新型的植物激素，由植物根系合成，可调控植株地上部与地下部的生长发育。我们此前的研究证实，合成的独脚金内酯类似物（strigolactone analogues）可强效抑制乳腺癌细胞及乳腺癌干细胞的增殖。本研究发现，独脚金内酯类似物能够抑制一系列涵盖实体瘤与非实体瘤的癌细胞系的生长与存活，包括前列腺癌、结肠癌、肺癌、黑色素瘤、骨肉瘤及白血病细胞系，而对正常细胞的影响微乎其微。此外，我们检测了患者配对的条件重编程正常细胞与前列腺癌细胞的响应情况。相较于对应的正常细胞，肿瘤细胞对两种活性最强的独脚金内酯类似物表现出显著更高的敏感性，且伴随凋亡水平升高。独脚金内酯类似物处理癌细胞后，其细胞特征为应激信号通路、细胞周期阻滞及凋亡相关基因的表达与活性上调。五种独脚金内酯类似物均可诱导G2/M期细胞周期阻滞，并伴随细胞周期蛋白B1（cyclin B1）的表达水平下调。细胞凋亡的特征为亚G1期细胞比例升高，这一结果通过Annexin V染色得到验证。在配对的条件重编程肿瘤与正常前列腺细胞中，聚腺苷二磷酸核糖聚合酶1（PARP1）的剪切片段检测证实了肿瘤细胞凋亡的特异性升高。综上，独脚金内酯类似物有望成为抗癌治疗的候选药物，其可在肿瘤细胞中特异性诱导细胞周期阻滞、细胞应激及凋亡，而对正常细胞的生长与存活仅产生极微弱的影响。本研究中每个实验条件均设置重复样本。U2OS细胞分别用两种独脚金内酯类似物ST362与MEB55处理，处理浓度为5 ppm，处理时间分别为6小时与24小时。对照组仅使用溶剂进行处理。