Content area
Full Text
Background
Cancer cells have been widely recognized for their inherent rewiring mechanism to utilize nutrients by robust and complex pathways [1, 2], which permits cancer growth and dissemination under constrained metabolic conditions in the microenvironment [3]. While the phenomenal observation of Otto Warburg and colleagues that tumor cells abnormally increased glucose uptake toward lactate production [4] placed glucose in the spotlight regarding cancer metabolism, numerous studies have also revealed remarkable changes in the metabolism of lipids and amino acid(s) [5, 6] and recently of semi-essential arginine [7, 8]. The early notions that arginine promoted tumorigenesis in patients [9] and that arginine preferably moved from blood to cancerous tissues [10] but not normal counterparts [11] have long implied the immense potential of this amino acid in tumor pathology. In parallel with its well-known function in the urea cycle, as one of the intermediates carrying ammonia to form urea [12], arginine has also been reported to serve as a precursor for polyamine and nitric oxide, both being permissive for cancer invasion [13, 14–15]. Thus, starving cells of arginine has been considered to be an appealing regime that is currently under clinical investigation for various types of cancer [16, 17, 18–19], including a successful phase 3 trial in mesothelioma [20]. Strikingly, tumors have been reported to acquire resistance to such treatment, although the underlying molecular mechanisms remained largely unclear [21].
Cancer cells become reliant on arginine when their excessive demand coincides with the impairment of intrinsic arginine production controlled by the rate-limiting enzyme argininosuccinate synthase 1 (ASS1) [13]. As its name suggested, intact ASS1 incorporates aspartate to citrulline to form argininosuccinate, the immediate precursor of arginine. This process supposedly nourishes cells with de novo synthesized arginine [12]. Of note, tumor cells evolved to favor the shunting of aspartate to nucleotide instead of arginine synthesis [22] following silencing of ASS1 [23, 24–25]. Paradoxically, upon arginine deprivation, resurgence of ASS1 has been reported and considered a direct mechanism of acquired resistance of cancer to therapy [26]. While transcription of ASS1 has been well established as occurring through several factors such as p53 [27, 28], c-MYC [29, 30–31], or hypoxia-inducible factor 1-alpha (Hif1α) [32], evidence on translational regulation of ASS1 is alarmingly missing.
Herein, we report the enhanced regulation of ASS1...