Sensitivity of Colorectal Cancer to Arginine Deprivation Therapy is Shaped by Differential Expression of Urea Cycle Enzymes

Constantinos Alexandrou, Saif Sattar Al-Aqbi, Jennifer A. Higgins, William Boyle, Ankur Karmokar, Catherine Andreadi, Jin-Li Luo, David A. Moore, Maria Viskaduraki, Matthew Blades, Graeme I. Murray, Lynne M. Howells, Anne Thomas, Karen Brown, Paul N. Cheng, Alessandro Rufini

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Abstract

Tumors deficient in the urea cycle enzymes argininosuccinate synthase-1 (ASS1) and ornithine transcarbamylase (OTC) are unable to synthesize arginine and can be targeted using arginine-deprivation therapy. Here, we show that colorectal cancers (CRCs) display negligible expression of OTC and, in subset of cases, ASS1 proteins. CRC cells fail to grow in arginine-free medium and dietary arginine deprivation slows growth of cancer cells implanted into immunocompromised mice. Moreover, we report that clinically-formulated arginine-degrading enzymes are effective anticancer drugs in CRC. Pegylated arginine deiminase (ADI-PEG20), which degrades arginine to citrulline and ammonia, affects growth of ASS1-negative cells, whereas recombinant human arginase-1 (rhArg1peg5000), which degrades arginine into urea and ornithine, is effective against a broad spectrum of OTC-negative CRC cell lines. This reflects the inability of CRC cells to recycle citrulline and ornithine into the urea cycle. Finally, we show that arginase antagonizes chemotherapeutic drugs oxaliplatin and 5-fluorouracil (5-FU), whereas ADI-PEG20 synergizes with oxaliplatin in ASS1-negative cell lines and appears to interact with 5-fluorouracil independently of ASS1 status. Overall, we conclude that CRC is amenable to arginine-deprivation therapy, but we warrant caution when combining arginine deprivation with standard chemotherapy.
Original languageEnglish
Article number12096
Pages (from-to)1-14
Number of pages14
JournalScientific Reports
Volume8
DOIs
Publication statusPublished - 14 Aug 2018

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Alexandrou, C., Al-Aqbi, S. S., Higgins, J. A., Boyle, W., Karmokar, A., Andreadi, C., Luo, J-L., Moore, D. A., Viskaduraki, M., Blades, M., Murray, G. I., Howells, L. M., Thomas, A., Brown, K., Cheng, P. N., & Rufini, A. (2018). Sensitivity of Colorectal Cancer to Arginine Deprivation Therapy is Shaped by Differential Expression of Urea Cycle Enzymes. Scientific Reports, 8, 1-14. [12096]. https://doi.org/10.1038/s41598-018-30591-7