Pereira Diane M, Gomes Sofia E, Borralho Pedro M, Rodrigues Cecília M P
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.
Cell Death Discov. 2019 Feb 11;5:68. doi: 10.1038/s41420-019-0150-1. eCollection 2019.
Colon cancer has been proposed to be sustained by a small subpopulation of stem-like cells with unique properties allowing them to survive conventional therapies and drive tumor recurrence. Identification of targetable signaling pathways contributing to malignant stem-like cell maintenance may therefore translate into new therapeutic strategies to overcome drug resistance. Here we demonstrated that MEK5/ERK5 signaling activation is associated with stem-like malignant phenotypes. Conversely, using a panel of cell line-derived three-dimensional models, we showed that ERK5 inhibition markedly suppresses the molecular and functional features of colon cancer stem-like cells. Particularly, pharmacological inhibition of ERK5 using XMD8-92 reduced the rate of primary and secondary sphere formation, the expression of pluripotency transcription factors SOX2, NANOG, and OCT4, and the proportion of tumor cells with increased ALDH activity. Notably, this was further associated with increased sensitivity to 5-fluorouracil-based chemotherapy. Mechanistically, ERK5 inhibition resulted in decreased expression and NF-κB transcriptional activity, suggesting a possible ERK5/NF-κB/IL-8 signaling axis regulating stem-like cell malignancy. Taken together, our results provide proof of principle that ERK5-targeted inhibition may be a promising therapeutic approach to eliminate drug-resistant cancer stem-like cells and improve colon cancer treatment.
有人提出，结肠癌是由一小群具有独特特性的干细胞样细胞维持的，这些特性使它们能够在传统治疗中存活并驱动肿瘤复发。因此，识别有助于维持恶性干细胞样细胞的可靶向信号通路可能会转化为克服耐药性的新治疗策略。在这里，我们证明了MEK5/ERK5信号激活与干细胞样恶性表型相关。相反，使用一组细胞系衍生的三维模型，我们表明抑制ERK5可显著抑制结肠癌干细胞样细胞的分子和功能特征。特别是，使用XMD8-92对ERK5进行药理学抑制降低了原发性和继发性球体形成率、多能性转录因子SOX2、NANOG和OCT4的表达，以及醛脱氢酶（ALDH）活性增加的肿瘤细胞比例。值得注意的是，这进一步与对基于5-氟尿嘧啶的化疗的敏感性增加相关。从机制上讲，抑制ERK5导致核因子κB（NF-κB）表达和转录活性降低，提示可能存在ERK5/NF-κB/白细胞介素-8（IL-8）信号轴调节干细胞样细胞恶性程度。综上所述，我们的结果提供了原理证明，即靶向抑制ERK5可能是一种有前景的治疗方法，可消除耐药性癌症干细胞样细胞并改善结肠癌治疗。
