Abstract 2648: L-arginine regulates chemotherapy sensitivity via ER stress and autophagic pathways in arginine prototrophic cancer cells
Authors: Gao Mingming , Wang Kathy He , Wang Qian , Liu Hao , Roman Valerie , Burn Timothy , Covington Maryanne , Koblish Holly , Shin Niu 
Published: September 2020

Abstract
Cancer patients have higher levels of arginase and lower levels of arginine in plasma than healthy subjects. The importance of arginine in maintaining the viability and function of T cells and NK cells is well established. Thus, inhibition of arginase to increase arginine is being investigated clinically as a potential immunotherapeutic approach for the treatment of cancer. Exogenous arginine is also known to be critical for arginine auxotrophic tumor cells which lack the expression of ASS1 and ASL, two key enzymes in the urea cycle that are responsible for the production of arginine. Accordingly, PEGylated arginase has been clinically tested to starve tumors that are arginine auxotrophic. However, the majority of tumor cells are arginine prototrophic based on the expression of ASS1 and ASL, and the effect of arginine on these cells has not been fully explored. In this study, we investigate the effect of exogenous arginine at the pathophysiologically relevant concentrations on the arginine prototrophic tumor cells. Compared to arginine at 100 μM (normal plasma concentration), arginine restriction at 20 μM (plasma concentration detected in some cancer patients) reduced the cell cycle S-phase entry and proliferation signaling in the cells of different tumor types. Importantly, the potencies of multiple chemotherapies, including oxaliplatin, 5-fluorouracil, gemcitabine, and cisplatin, were also reduced by the lower level of arginine (up to ~270 fold) in these tumor cells. In line with the well-established negative correlation between ER stress and autophagy and sensitivity to chemotherapies, we found that L-arginine restriction stimulated the eIF2α/ATF4/CHOP signaling axis, suggesting activation of integrated stress response, ER stress, and autophagic pathways. Blockade of autophagy using either 3-methyladenine, an inhibitor of early stage autophagy, or hydroxychloroquine, an inhibitor of late stage autophagy, partially reduced the arginine restriction-induced chemo-resistance in the cancer cells. Taken together, these data suggest that reduction in arginine through enhanced arginase activity in the tumor microenvironment may represent a metabolic response by the host to slow tumor growth, with the inhibitory effect on the anti-tumor function of immune cells being an unfortunate collateral consequence. Elevating arginine by arginase inhibition may not only take away the metabolic brake on immune cells, but also help restore the sensitivity of tumor cells to chemotherapies.
Citation Format: Mingming Gao, Kathy He Wang, Qian Wang, Hao Liu, Valerie Roman, Timothy Burn, Maryanne Covington, Holly Koblish, Niu Shin. L-arginine regulates chemotherapy sensitivity via ER stress and autophagic pathways in arginine prototrophic cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2648.