The impact of arginine deprivation on cancer cell viability and signaling pathways associated with hypoxia

Some cancer types are auxotrophic for arginine and rely on delivery of this amino acid from extracellular sources. This cellular inferiority has been used to design selective anticancer therapy based on the enzymatic arginine depletion. However, deprivation of arginine as a single treatment was less effective in clinical trials than was expected. One of the approaches to improve anticancer efficacy of arginine deprivation is to simultaneously target signaling pathways that support cell survival upon the lack of arginine. Thus, the aim of this study was to investigate the effect of hypoxia signaling in arginine-deprived cancer cells. For this purpose, human cancer cell lines were maintained in arginine-supplied or in arginine-deplete media. Hypoxic condition was mimic by addition of 0.1 and 0.2 mM cobalt (II) chloride (CoCl 2 ) that protect HIF-1α from degradation. It was shown that arginine starvation alone induced expression of VEGF-A, which allow us to hypothesize involvement of hypoxic signaling pathways in cell repose to the lack of arginine. We did not detect any significant impact of CoCl 2 on mTOR signaling and unfolded protein response pathways in cells maintained in bouth conditions. Instead, CoCl 2 inhibited p38-MAPK signaling pathway in cancer cells incubated in arginine-supplied medium. At the same time, additional exposure of the tested arginine-deprived cancer cells to CoCl 2 did not further reduce cell viability and promote caspase-dependent apoptosis. To sum up, the artificial enhancement of hypoxia did not increase cytotoxicity of arginine deprivation towards the tested human cancer cells, this approach demands further investigations.