Tumor Metabolism

Reprogramming Arginine Metabolism for Cancer Prevention and Treatment

Arginine is a semi-essential amino acid, and the level is largely dependent on the dietary intake1. Arginine is metabolized into multiple products, including NO, creatine, polyamines and proline, all of which play critical roles in cell survival and growth2.  Among all, the major metabolic pathways are nitric oxide (NO) production by nitric oxide synthase (NOS) and the synthesis of polyamines, small polycationic metabolites, initiated by arginase (ARG). The two pathways antagonize each other to maintain the balance between the two metabolites.  In cancer, however, arginine metabolism tends to be shunted into polyamine-synthesis pathways, since polyamines are essential for tumor cell growth, proliferation and immuno-suppression3-6.  In the tumor microenvironment, polyamines help expand the populations of immune-suppressive immune cells5.  In addition, tumor-associated macrophages (TAMs), which are predominantly polarized to the immuno-suppressive M2-type, produce polyamines to contribute to the immuno-suppressive tumor microenvironment7. 

Aiming to correct arginine metabolism in cancer cells and microenvironment, we’ve sought to redirect arginine usage towards NO synthesis pathway. To this end, we provide patients with dietary supplements or FDA-approved metabolic modulators to improve the NOS function and to suppress polyamine production. We found that this approach robustly converts M2-type TAMs (immunosuppressive, polyamine-producing) to M1-type TAMs (immuno-stimulatory, NO-producing), while also suppressing tumor growth8. 

REFERENCES

1          Tapiero, H., Mathé, G., Couvreur, P. & Tew, K. D. I. Arginine. Biomedicine & Pharmacotherapy 56, 439-445 (2002).

2          Keshet, R. & Erez, A. Arginine and the metabolic regulation of nitric oxide synthesis in cancer. Dis Model Mech. 11, pii: dmm033332 (2016).

3          Thomas, T. & Thomas, T. J. Polyamine metabolism and cancer. J Cell Mol Med 7, 113-126 (2003).

4          Hayes, C. S. et al. Polyamine-blocking therapy reverses immunosuppression in the tumor microenvironment. Cancer Immunol Res. 2, 274-285 (2014).

5          Alexander, E. T., Minton, A., Peters, M. C., Phanstiel, O. t. & Gilmour, S. K. A novel polyamine blockade therapy activates an anti-tumor immune response. Oncotarget 8, 84140-84152 (2017).

6          Kus, K. et al. Alterations in arginine and energy metabolism, structural and signalling lipids in metastatic breast cancer in mice detected in plasma by targeted metabolomics and lipidomics. Breast Cancer Res 20, 148 (2018).

7          Mills, C. D., Lenz, L. L. & Ley, K. Macrophages at the fork in the road to health or disease. Front. Immunol. 6, 59 (2015).

8          Zheng, X. et al. Correction of arginine metabolism with sepiapterin-the precursor of nitric oxide synthase cofactor BH(4)-induces immunostimulatory-shift of breast cancer. Biochem Pharmacol 176, 113887, doi:10.1016/j.bcp.2020.113887 (2020).