Direct inhibition of STAT signaling by platinum drugs contributes to their anti-cancer activity

被引:14
作者
Hato, Stanleyson V. [1 ]
Figdor, Carl G.
Takahashi, Susumu
Pen, Anja E.
Halilovic, Altuna [3 ]
Bol, Kalijn F. [5 ]
Vasaturo, Angela
Inoue, Yukie
de Haas, Nienke [5 ]
Verweij, Dagmar [3 ,4 ,5 ]
Van Herpen, Carla M. L. [2 ]
Kaanders, Johannes H. [3 ]
van Krieken, Johan H. J. M. [1 ,4 ]
Van Laarhoven, Hanneke W. M. [2 ,4 ,5 ]
Hooijer, Gerrit K. J. [3 ]
Punt, Cornelis J. A. [1 ]
Asai, Akira [2 ]
de Vries, I. Jolanda M.
Lesterhuis, W. Joost
机构
[1] Radboud Univ Med Ctr & Radboud Inst Mol Life Sci, Dept Tumor Immunol, Nijmegen, Netherlands
[2] Radboud Univ Med Ctr & Radboud Inst Mol Life Sci, Dept Pathol, Nijmegen, Netherlands
[3] Radboud Univ Med Ctr & Radboud Inst Mol Life Sci, Dept Med Oncol, Nijmegen, Netherlands
[4] Radboud Univ Med Ctr & Radboud Inst Mol Life Sci, Dept Radiat Oncol, Nijmegen, Netherlands
[5] Univ Amsterdam, Acad Med Ctr, Dept Med Oncol, Amsterdam, Netherlands
基金
英国医学研究理事会;
关键词
platinum chemotherapy; STAT signaling; SH2; domain; cancer; STAT3; ANTITUMOR-ACTIVITY; CANCER-CELLS; CISPLATIN; MODULATION; ACTIVATION; CHEMOTHERAPEUTICS; TRANSCRIPTION; RESISTANCE; APOPTOSIS;
D O I
10.18632/oncotarget.17661
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 in vitro 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 (n = 65) or with radiotherapy alone (n = 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 phosphotyrosine 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 (p = 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.
引用
收藏
页码:54434 / 54443
页数:10
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