Arginine starvation in colorectal carcinoma cells: Sensing, impact on translation control and cell cycle distribution

• Published in: Experimental cell research Vol. 341; no. 1; pp. 67 - 74
• Main Authors: Vynnytska-Myronovska, Bozhena O., Kurlishchuk, Yuliya, Chen, Oleh, Bobak, Yaroslav, Dittfeld, Claudia, Hüther, Melanie, Kunz-Schughart, Leoni A., Stasyk, Oleh V.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2016; Elsevier BV
• Subjects: 60 APPLIED LIFE SCIENCES; ARGININE; Arginine - metabolism; Arginine starvation; BIOLOGICAL STRESS; CARCINOMAS; CELL CYCLE; CELL PROLIFERATION; Cellular biology; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; FASTING; GCN2 pathway; HCT116 Cells; HT29 Cells; Humans; INHIBITION; Intracellular arginine level; MATERIALS RECOVERY; mTOR signaling; MUTANTS; NUTRIENTS; p53 status; Protein Biosynthesis; PROTEINS; REGULATIONS; Signal Transduction; SIGNALS; TOR Serine-Threonine Kinases - metabolism; TUMOR CELLS; Tumor Cells, Cultured; Tumor Suppressor Protein p53 - metabolism; Tumors; Intracellular arginine level; p53 status; Arginine starvation; mTOR signaling; GCN2 pathway; Colorectal carcinoma
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2016.01.002

Tumor cells rely on a continued exogenous nutrient supply in order to maintain a high proliferative activity. Although a strong dependence of some tumor types on exogenous arginine sources has been reported, the mechanisms of arginine sensing by tumor cells and the impact of changes in arginine availability on translation and cell cycle regulation are not fully understood. The results presented herein state that human colorectal carcinoma cells rapidly exhaust the internal arginine sources in the absence of exogenous arginine and repress global translation by activation of the GCN2-mediated pathway and inhibition of mTOR signaling. Tumor suppressor protein p53 activation and G1/G0 cell cycle arrest support cell survival upon prolonged arginine starvation. Cells with the mutant or deleted TP53 fail to stop cell cycle progression at defined cell cycle checkpoints which appears to be associated with reduced recovery after durable metabolic stress triggered by arginine withdrawal. •Arginine withdrawal causes a rapid and dramatic drop of its intracellular level.•Starvation for arginine activates GCN2 and decreases mTOR cellular signaling.•Response to arginine starvation depends on p53 status of the cells.