Abstract
BackgroundIonizing 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.MethodsLOX-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.ResultsLOX 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.ConclusionsThese 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.
Highlights
Ionizing radiation (IR) is a mainstay of cancer therapy, but irradiation can at times lead to stress responses, which counteract IR-induced cytotoxicity
We investigate the effects of IR on lysyl oxidase (LOX) secretion by tumor cells to determine a putative role in an IRinduced stress response, which might promote treatment resistance
Ionizing radiation promotes LOX-secretion by tumor cells To explore the cellular stress response to ionizing radiation (IR) with regard to LOX, human A459 lung adenocarcinoma cells were irradiated with increasing doses of IR. 16-20 hours after irradiation, the amount and the enzymatic activity of LOX secreted into conditioned medium (CM) were determined by western blotting, ELISA and a fluorometric activity assay, respectively
Summary
Ionizing radiation (IR) is a mainstay of cancer therapy, but irradiation can at times lead to stress responses, which counteract IR-induced cytotoxicity. Lysyl oxidase (LOX) is a cell-secreted amine oxidase that crosslinks collagen and elastin in the extracellular space, resulting in increased tissue stiffness and tensile strength. It is secreted as an inactive 50 kDa proenzyme and cleaved extracellularly to a 32 kDa active enzyme [21,22]. LOX promotes tumor growth and progression in vivo, cancer cell invasion, and premetastatic niche formation to foster distant metastases [22,27,28,29,30]. We investigate the effects of IR on LOX secretion by tumor cells to determine a putative role in an IRinduced stress response, which might promote treatment resistance. Our expression and combined treatment studies with microtubule-stabilizing agents suggest that LOX expression and secretion are differentially regulated by hypoxia and ionizing radiation
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
