Canavanine dysregulates cellular signaling and represses ASS1 under arginine deprivation in colorectal carcinoma cells

Metabolic arginine (Arg) deprivation therapy (ADT) has been evaluated as a treatment for a number of cancer entities deficient in Arg conversion from its anabolic precursors, including colorectal carcinomas (CRC). Several ADT-based combination treatments have been proposed that potentially bear the improved efficacy. Here we report on the molecular effects of cytotoxic proteinogenic Arg analogue of plant origin canavanine (Cav) and demonstrate that it mimics Arg in several regulatory pathways including those involved in transcriptional silencing of argininosuccinate synthetase 1 (ASS1) – an enzyme of the urea cycle, Arg anabolism, and a key determinant of cancer cells’ sensitivity to ADT. We observed that Cav represses ASS1 transcription in Arg-starved CRC cells in a c-Myc-independent manner. It was also established that pre-exposure to ADT additionally sensitizes CRC cells to cytotoxic effects of Cav. These in vitro findings may provide new avenues to resolve the main shortcomings of ADT and lead to improved metabolic therapeutic modalities for CRC and other cancers.