l -Arginine Uptake and Its Role in the Survival of Breast Cancer Cells

l-Arginine is an essential amino acid that plays a critical role in the growth of breast cancer cells. l-Arginine may be derived intracellularly through biosynthesis or extracellularly from diverse sources such as the culture medium in vitro, the diet in vivo, and proteolysis of extracellular polypeptide substrates both in vitro and in vivo. l-Arginine, transported into the cell by cationic amino acid transporters (CATs), is the common substrate of two enzymes, arginase and nitric oxide synthase, for the production of ornithine and nitric oxide (NO), respectively (Fig. 20.1). Ornithine is the precursor of polyamines that are essential for cell proliferation. NO has many physiological and pathophysiological functions, including modulation of cancer cell growth. We have reported that breast cancer cells express several System y+ CATs (Abdelmagid et al., J Cell Biochem 112:1084–1092, 2011). We have also reported that a plasma membrane-bound metalloproteinase, carboxypeptidase-D (CPD), cleaves C-terminal l-arginine residues from extracellular substrates for NO production in cancer cells (Abdelmagid and Too, Endocrinology 149:4821–4828, 2008; Thomas et al., Prostate 72:450–460, 2012) (Fig. 20.1). This chapter presents our studies on the role of System y+ carrier CAT-1 in the uptake of l-arginine in breast cancer cells. Our studies also show that CPD, through its extracellular cleavage of l-arginine, plays a significant role in the intracellular production of NO for the survival of cancer cells. Furthermore, this CPD–arginine–NO pathway is stimulated by hormones, 17β-estradiol, prolactin, and androgens in breast cancer cells, thereby implicating its potential usefulness as a therapeutic target, not only for the modulation of NO levels but also for endocrine therapy in breast cancer.