Hato Stanleyson V, Figdor Carl G, Takahashi Susumu, Pen Anja E, Halilovic Altuna, Bol Kalijn F, Vasaturo Angela, Inoue Yukie, de Haas Nienke, Verweij Dagmar, Van Herpen Carla M L, Kaanders Johannes H, van Krieken Johan H J M, Van Laarhoven Hanneke W M, Hooijer Gerrit K J, Punt Cornelis J A, Asai Akira, de Vries I Jolanda M, Lesterhuis W Joost
Department of Tumor Immunology, Radboud University Medical Centre and Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
Center for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
Oncotarget. 2017 May 7;8(33):54434-54443. doi: 10.18632/oncotarget.17661. eCollection 2017 Aug 15.
Platinum-based chemotherapeutics are amongst the most powerful anti-cancer drugs. Although their exact mechanism of action is not well understood, it is thought to be mediated through covalent DNA binding. We investigated the effect of platinum-based chemotherapeutics on signaling through signal transducer and activator of transcription (STAT) proteins, which are involved in many oncogenic signaling pathways. We performed experiments in various cancer cell lines, investigating the effects of platinum chemotherapeutics on STAT phosphorylation and nuclear translocation, the expression of STAT-modulating proteins and downstream signaling pathways. Direct binding of platinum to STAT proteins was assessed using an AlphaScreen assay. Nuclear STAT3 expression was determined by immunohistochemistry and correlated with disease-free survival in retrospective cohorts of head and neck squamous cell carcinoma (HNSCC) patients treated with cisplatin-based chemoradiotherapy ( 65) or with radiotherapy alone ( = 32). At clinically relevant concentrations, platinum compounds inhibited STAT phosphorylation, resulting in loss of constitutively activated STAT proteins in multiple distinct cancer cell lines. Platinum drugs specifically inhibited phospho-tyrosine binding to SH2 domains, thereby blocking STAT activation, and subsequently downregulating pro-survival- and anti-apoptotic- target genes. Importantly, we found that active STAT3 in tumors directly correlated with response to cisplatin-based chemoradiotherapy in HNSCC patients ( = 0.006). These findings provide insight into a novel, non-DNA-targeted mechanism of action of platinum drugs, and could be leveraged into the use of STAT expression as predictive biomarker for cisplatin chemotherapy and to potentiate other therapeutic strategies such as immunotherapy.
铂类化疗药物是最有效的抗癌药物之一。尽管其确切作用机制尚不完全清楚，但据认为是通过与DNA共价结合介导的。我们研究了铂类化疗药物对信号转导和转录激活因子（STAT）蛋白信号传导的影响，STAT蛋白参与许多致癌信号通路。我们在多种癌细胞系中进行了实验，研究铂类化疗药物对STAT磷酸化和核转位、STAT调节蛋白的表达以及下游信号通路的影响。使用AlphaScreen分析评估铂与STAT蛋白的直接结合。通过免疫组织化学测定核STAT3表达，并与接受顺铂同步放化疗（n = 65）或单纯放疗（n = 32）的头颈部鳞状细胞癌（HNSCC）患者回顾性队列中的无病生存期相关联。在临床相关浓度下，铂化合物抑制STAT磷酸化，导致多种不同癌细胞系中组成性激活的STAT蛋白丧失。铂类药物特异性抑制磷酸酪氨酸与SH2结构域的结合，从而阻断STAT激活，并随后下调促生存和抗凋亡靶基因。重要的是，我们发现肿瘤中活性STAT3与HNSCC患者对顺铂同步放化疗的反应直接相关（P = 0.006）。这些发现为铂类药物一种新的非DNA靶向作用机制提供了见解，并可用于将STAT表达用作顺铂化疗的预测生物标志物，以及增强其他治疗策略，如免疫治疗。
