Topoisomerase inhibitors promote cancer cell motility via ROS-mediated activation of JAK2-STAT1-CXCL1 pathway

Jiafei Liu,Chengchao Shou,Like Qu,Lin Meng

doi:10.1186/s13046-019-1353-2

Abstract

BackgroundTopoisomerase inhibitors (TI) can inhibit cell proliferation by preventing DNA replication, stimulating DNA damage and inducing cell cycle arrest. Although these agents have been commonly used in the chemotherapy for the anti-proliferative effect, their impacts on the metastasis of cancer cells remain obscure.MethodsWe used the transwell chamber assay to test effects of Topoisomerase inhibitors Etoposide (VP-16), Adriamycin (ADM) and Irinotecan (CPT-11) on the migration and invasion of cancer cells. Conditioned medium (CM) from TI-treated cells was subjected to Mass spectrometry screening. Gene silencing, neutralizing antibody, and specific chemical inhibitors were used to validate the roles of signaling molecules.ResultsOur studies disclosed that TI could promote the migration and invasion of a subset of cancer cells, which were dependent on chemokine (C-X-C motif) ligand 1 (CXCL1). Further studies disclosed that TI enhanced phosphorylation of Janus kinase 2 (JAK2) and Signal transducers and activators of transcription 1 (STAT1). Silencing or chemical inhibition of JAK2 or STAT1 abrogated TI-induced CXCL1 expression and cell motility. Moreover, TI increased cellular levels of reactive oxygen species (ROS) and promoted oxidation of Protein Tyrosine Phosphatase 1B (PTP1B), while reduced glutathione (GSH) reversed TI-induced JAK2-STAT1 activation, CXCL1 expression, and cell motility.ConclusionsOur study demonstrates that TI can promote the expression and secretion of CXCL1 by elevating ROS, inactivating PTP1B, and activating JAK2-STAT1 signaling pathway, thereby promoting the motility of cancer cells.

Highlights

Topoisomerase inhibitors (TI) can inhibit cell proliferation by preventing DNA replication, stimulating DNA damage and inducing cell cycle arrest
We further demonstrated that TIpromoted cell motility is regulated by Janus kinase 2 (JAK2)-STAT1CXCL1 pathway, which is associated with reactive oxygen species (ROS)-induced Protein Tyrosine Phosphatase 1B (PTP1B) oxidization
These results suggest that VP-16, ADM and CPT-11 promote motility of a subset of cancer cells in vitro and in vivo

Summary

Introduction

Topoisomerase inhibitors (TI) can inhibit cell proliferation by preventing DNA replication, stimulating DNA damage and inducing cell cycle arrest. These agents have been commonly used in the chemotherapy for the anti-proliferative effect, their impacts on the metastasis of cancer cells remain obscure. Cyclophosphamide induces metastasis in the peripheral vessels of fibrosarcoma [7] Another chemotherapeutic agent, Carboplatin, could increase metastasis of melanoma to lung in mice [8]. Metastasis of breast cancer cells in lung has been found to Several mechanisms have been proposed to explain chemotherapy-induced metastasis. Paclitaxel drives metastasis in mouse models of breast cancer, which is dependent on stress-inducible gene Atf of non-cancer host cells [10].

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