Arginine Starvation Impairs Mitochondrial Respiratory Function in ASS1-Deficient Breast Cancer Cells

Abstract

Autophagy is the principal catabolic response to nutrient starvation and is necessary to clear dysfunctional or damaged organelles, but excessive autophagy can be cytotoxic or cytostatic and contributes to cell death. Depending on the abundance of enzymes involved in molecule biosynthesis, cells can be dependent on uptake of exogenous nutrients to provide these molecules. Argininosuccinate synthetase 1 (ASS1) is a key enzyme in arginine biosynthesis, and its abundance is reduced in many solid tumors, making them sensitive to external arginine depletion. We demonstrated that prolonged arginine starvation by exposure to ADI-PEG20 (pegylated arginine deiminase) induced autophagy-dependent death of ASS1-deficient breast cancer cells, because these cells are arginine auxotrophs (dependent on uptake of extracellular arginine). Indeed, these breast cancer cells died in culture when exposed to ADI-PEG20 or cultured in the absence of arginine. Arginine starvation induced mitochondrial oxidative stress, which impaired mitochondrial bioenergetics and integrity. Furthermore, arginine starvation killed breast cancer cells in vivo and in vitro only if they were autophagy-competent. Thus, a key mechanism underlying the lethality induced by prolonged arginine starvation was the cytotoxic autophagy that occurred in response to mitochondrial damage. Last, ASS1 was either low in abundance or absent in more than 60% of 149 random breast cancer bio-samples, suggesting that patients with such tumors could be candidates for arginine starvation therapy.

Arginine deprivation using pegylated arginine deiminase has activity against primary acute myeloid leukemia cells in vivo

“…Studies in other malignancies have shown a similar correlation between ASS1 expression and sensitivity to arginine deprivation. 8,9 The leukemic stem cell compartment did not show higher expression of ASS1 than the bulk of AML cells. By contrast, there was heterogeneity of ASS1 expression in normal human bone marrow cells.…”

“…[4][5][6] ASS1 is not expressed by many malignant cells, and this appears to confer a proliferative advantage to the cells. [7][8][9] Overexpression and silencing of ASS1 in cancer cell lines reduce and increase proliferation, respectively. 8,9 The survival of patients with cancer that does not express ASS1 is worse than for patients whose tumors express ASS1.…”

“…[7][8][9] Overexpression and silencing of ASS1 in cancer cell lines reduce and increase proliferation, respectively. 8,9 The survival of patients with cancer that does not express ASS1 is worse than for patients whose tumors express ASS1. [7][8][9] Tumor cells that lack ASS1 are therefore dependent on exogenous arginine, which in normal circumstances is available from the extracellular environment.…”

“…8,9 The survival of patients with cancer that does not express ASS1 is worse than for patients whose tumors express ASS1. [7][8][9] Tumor cells that lack ASS1 are therefore dependent on exogenous arginine, which in normal circumstances is available from the extracellular environment. [4][5][6] However, ASS1-negative tumor cells are potentially vulnerable to systemic arginine depletion, having no means to synthesize their own.…”

The therapy of gefitinib towards breast cancer partially through reversing breast cancer biomarker arginine

“…The decrease of arginine in serum indicated possible elevation of arginine in tumor tissues. Previous literature showed that arginine starvation could protect breast cancer cells through impairing mitochondrial respiratory function 7 . Therefore, gefitinib-induced elevation of arginine in serum for gefitinib-treated patients might indicate the possible therapy role through decreasing the arginine level in tumor tissues.…”