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Open Access Highly Accessed Research article

Ionizing radiation induces tumor cell lysyl oxidase secretion

Colette J Shen12, Ashish Sharma1, Dinh-Van Vuong1, Janine T Erler3, Martin Pruschy1* and Angela Broggini-Tenzer1

Author Affiliations

1 Laboratory for Molecular Radiobiology, University Hospital Zurich, 8091 Zürich, Switzerland

2 Raymond and Ruth Perelman School of Medicine, University of Pennsylvania, 19104 Philadelphia, PA, USA

3 Biotech Research & Innovation Centre (BRIC), University of Copenhagen, 2200 Copenhagen, Denmark

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BMC Cancer 2014, 14:532  doi:10.1186/1471-2407-14-532

Published: 22 July 2014

Abstract

Background

Ionizing radiation (IR) is a mainstay of cancer therapy, but irradiation can at times also lead to stress responses, which counteract IR-induced cytotoxicity. IR also triggers cellular secretion of vascular endothelial growth factor, transforming growth factor β and matrix metalloproteinases, among others, to promote tumor progression. Lysyl oxidase is known to play an important role in hypoxia-dependent cancer cell dissemination and metastasis. Here, we investigated the effects of IR on the expression and secretion of lysyl oxidase (LOX) from tumor cells.

Methods

LOX-secretion along with enzymatic activity was investigated in multiple tumor cell lines in response to irradiation. Transwell migration assays were performed to evaluate invasive capacity of naïve tumor cells in response to IR-induced LOX. In vivo studies for confirming IR-enhanced LOX were performed employing immunohistochemistry of tumor tissues and ex vivo analysis of murine blood serum derived from locally irradiated A549-derived tumor xenografts.

Results

LOX was secreted in a dose dependent way from several tumor cell lines in response to irradiation. IR did not increase LOX-transcription but induced LOX-secretion. LOX-secretion could not be prevented by the microtubule stabilizing agent patupilone. In contrast, hypoxia induced LOX-transcription, and interestingly, hypoxia-dependent LOX-secretion could be counteracted by patupilone. Conditioned media from irradiated tumor cells promoted invasiveness of naïve tumor cells, while conditioned media from irradiated, LOX- siRNA-silenced cells did not stimulate their invasive capacity. Locally applied irradiation to tumor xenografts also increased LOX-secretion in vivo and resulted in enhanced LOX-levels in the murine blood serum.

Conclusions

These results indicate a differential regulation of LOX-expression and secretion in response to IR and hypoxia, and suggest that LOX may contribute towards an IR-induced migratory phenotype in sublethally-irradiated tumor cells and tumor progression.

Keywords:
Lysyl oxidase; Ionizing radiation; Tumor invasion; Radiation resistance; Hypoxia; Microtubule stabilizing agent