Abstract
The hypoxic tumour microenvironment represents an aggressive, therapy-resistant compartment. As arginine is required for specific hypoxia-induced processes, we hypothesised that arginine-deprivation therapy may be useful in targeting hypoxic cancer cells. We explored the effects of the arginine-degrading agent ADI-PEG20 on hypoxia-inducible factor (HIF) activation, the hypoxia-induced nitric oxide (NO) pathway and proliferation using HCT116 and UMUC3 cells and xenografts. The latter lack argininosuccinate synthetase (ASS1) making them auxotrophic for arginine. In HCT116 cells, ADI-PEG20 inhibited hypoxic-activation of HIF-1α and HIF-2α, leading to decreased inducible-nitric oxide synthase (iNOS), NO-production, and VEGF. Interestingly, combining hypoxia and ADI-PEG20 synergistically inhibited ASS1. ADI-PEG20 inhibited mTORC1 and activated the unfolded protein response providing a mechanism for inhibition of HIF and ASS1. ADI-PEG20 inhibited tumour growth, impaired hypoxia-associated NO-production, and decreased vascular perfusion. Expression of HIF-1α/HIF-2α/iNOS and VEGF were reduced, despite an increased hypoxic tumour fraction. Similar effects were observed in UMUC3 xenografts. In summary, ADI-PEG20 inhibits HIF-activated processes in two tumour models with widely different arginine biology. Thus, ADI-PEG20 may be useful in the clinic to target therapy-resistant hypoxic cells in ASS1-proficient tumours and ASS1-deficient tumours.
Highlights
The hypoxic tumour microenvironment represents an aggressive, therapy-resistant compartment
To examine potential interactions between arginine-deprivation and hypoxia, we explored the effect of ADI-PEG20 on hypoxia-induced hypoxia-inducible factor (HIF)-α protein
The inhibitory effects of ADI-PEG20 on HIF-activation were further confirmed by analysis of additional HIF-downstream targets, carbonic anhydrase-IX (CA-IX) and glucose transporter-1 (GLUT-1), both of which were reduced (Fig. 1A)
Summary
The hypoxic tumour microenvironment represents an aggressive, therapy-resistant compartment. We explored the effects of the argininedegrading agent ADI-PEG20 on hypoxia-inducible factor (HIF) activation, the hypoxia-induced nitric oxide (NO) pathway and proliferation using HCT116 and UMUC3 cells and xenografts. The latter lack argininosuccinate synthetase (ASS1) making them auxotrophic for arginine. In HCT116 cells, ADI-PEG20 inhibited hypoxic-activation of HIF-1α and HIF-2α, leading to decreased inducible-nitric oxide synthase (iNOS), NO-production, and VEGF. Well-recognised effects of hypoxia include altered cell metabolism[5,6], increased NO synthesis via induction of iNOS, and increased VEGF expression These are orchestrated by the transcription factors HIF-1 and HIF-2, which regulate the expression of many genes involved in tumour biology[7,8]. We assessed the effect of ADI-PEG20 on ASS1-deficient UMUC3 xenografts to compare the effects in ASS1-proficient and deficient tumours
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