Research Papers:
Direct inhibition of STAT signaling by platinum drugs contributes to their anti-cancer activity
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Abstract
Stanleyson V. Hato1, Carl G. Figdor1, Susumu Takahashi5, Anja E. Pen1, Altuna Halilovic2, Kalijn F. Bol1,3, Angela Vasaturo1, Yukie Inoue5, Nienke de Haas1, Dagmar Verweij2, Carla M.L. Van Herpen3, Johannes H. Kaanders4, Johan H.J.M. van Krieken2, Hanneke W.M. Van Laarhoven6, Gerrit K.J. Hooijer6, Cornelis J.A. Punt6, Akira Asai5, I. Jolanda M. de Vries1,3 and W. Joost Lesterhuis1,3,7
1Department of Tumor Immunology, Radboud University Medical Centre and Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands
2Department of Pathology, Radboud University Medical Centre and Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands
3Department of Medical Oncology, Radboud University Medical Centre and Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands
4Department of Radiation Oncology, Radboud University Medical Centre and Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands
5Center for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
6Department of Medical Oncology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
7Current address: University of Western Australia, School of Medicine and Pharmacology, Perth, Australia
Correspondence to:
W. Joost Lesterhuis, email: [email protected]
Stanleyson V. Hato, email: [email protected]
Keywords: platinum chemotherapy, STAT signaling, SH2 domain, cancer, STAT3
Received: September 02, 2016 Accepted: April 22, 2017 Published: May 07, 2017
ABSTRACT
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 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 (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.
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