Arginine deprivation and autophagic cell death in cancer

Our increasing awareness over the last decade, that reprogramming of cellular energetics is a key hallmark of tumorigenesis, has reinvigorated the search for novel tractable metabolic targets in cancer cells (1). From innovative diagnostics based on the tracer 18F-deoxyglucose in positron emission tomography (FDG-PET) to the development of next-generation antimetabolites built on l-asparaginase, methotrexate, and 5-fluorouracil, there is excitement that a deeper understanding of tumor metabolism will revolutionize patient care (2). Modulating the key substrates glucose and glutamine has great appeal because these provide the essential carbon source for many anabolic cellular processes required during tumor growth (3). However, it has become apparent that there are many other metabolites fueling tumorigenesis. These metabolites range from the rare “oncometabolite” 2-HG in isocitrate dehydrogenase mutant tumors to critical roles for a wider array of amino acids, including serine, glycine, proline, and especially arginine (4⇓⇓–7). Targeting arginine has been the focus of preclinical and promising clinical activity driven by the availability of novel arginine depletors and an appreciation that a range of hematological and solid cancers are defective in urea cycle enzymes, namely argininosuccinate synthetase 1 (ASS1) and argininosuccinate lyase (8, 9). Arginine is a highly versatile amino acid required for the synthesis of proteins, nitric oxide, polyamines, nucleotides, agmatine, creatine, proline, and glutamate. In particular, deficiency of the tumor suppressor ASS1—frequently caused by methylation of the gene promoter—confers a worse prognosis and sensitizes tumors to arginine starvation with pegylated arginine deiminase (ADI-PEG20) and human recombinant arginase (10⇓⇓–13). Arginine withdrawal leads to increased protein turnover—via reduced synthesis and increased breakdown [suppression of mammalian target of rapamycin (mTOR) and proteosomal degradation, respectively]—and triggers caspase-dependent and caspase-independent apoptotic cell death in a cell type-dependent manner (13⇓–15). In PNAS, Changou et al. …