Proline Maintains the Proliferation of Hepatocellular Carcinoma Cells by Decreasing Intracellular Oxidative Stress and Reducing Autophagy During Acute Nutrient Stress

Abstract

Purpose Malignant tumour cell proliferation has high nutritional requirements and leads to nutrient depletion in local tumour tissues. Metabolic reprogramming under nutritional stress is essential for malignant tumour cell proliferation. Proline metabolism contributes to cancer cell proliferation and invasion, but the underlying mechanisms remain unclear. The aim of this study was to investigate the mechanisms whereby proline maintains hepatocellular carcinoma (HCC) cell proliferation. Methods The Cancer Genome Atlas database was used to compare expression of proteins related to proline metabolism between HCC and para-carcinoma tissues. Lipid droplet analysis in HCC cell lines was conducted to examine the effects of proline supplementation on lipid accumulation, and autophagic flux and protein expression were assessed to evaluate proline-mediated regulation of autophagy. Flow cytometry was used to determine intracellular levels of reactive oxygen species following proline addition. Results The expression of proline-metabolism-related proteins was significantly higher in HCC tissues than in para-carcinoma tissues. Proline supplementation eliminated the inhibition of HCC cell growth caused by nutrient deficiencies. Proline significantly reduced lipid droplet accumulation and inhibited autophagy under conditions of acute nutrient stress by maintaining the redox balance. Conclusion Proline plays an important role in regulating HCC cell survival under conditions of nutrient deficiency and represents a potential target for adjunctive cancer therapy.