Oxidative Stress and Metabolic Reprogramming in Cr(VI) Carcinogenesis

Abstract

Cr(VI)-containing compounds are well-established lung carcinogens. Chronic exposure of the normal human epithelial cells is able to induce malignant cell transformation, the first stage of metal carcinogenesis. These Cr(VI)-transformed cells exhibit increased level of antioxidants, reduced capacity of generating reactive oxygen species (ROS), and development of apoptosis resistance, promoting tumorigenesis of Cr(VI)-transformed cells, the second stage of metal carcinogenesis. The mechanism of Cr(VI) induced carcinogenesis is still under investigation. Recent studies indicate that ROS play a positive role in the first stage while a negative role in the second stage. Transformed cells adapt metabolism to support tumor initiation and progression. Altered metabolic activities directly participate in the process of cell transformation or support a large requirement for nucleotides, amino acids, and lipids for tumor growth. In malignantly Cr(VI)-transformed cells, mitochondrial oxidative phosphorylation is defective, and pentose phosphate pathway, glycolysis, and glutaminolysis are upregulated. These metabolic reprogramming supports rapid cell proliferation and contributes to tumorigenesis of Cr(VI)-transformed cells. This article summarizes the current progress in the studies of metabolic reprogramming and Cr(VI) carcinogenesis with emphasis on the metabolic enzymes and oxidative stress related major oncogenic pathways.

Keywords: Carcinogenesis; Chromium (VI); Oxidative stress; metabolic reprogramming.

Figure 1. Representative scheme of metabolic reprogramming in Cr(VI) carcinogenesis

Chronic exposure of cells to Cr(VI) causes ROS generation which is responsible for malignant cell transformation. Once the cells are malignant transformed, those cells exhibit activated PI3K/Akt, reduced ROS generation, and elevated levels of antioxidants and HIF-1α, resulting in reduction of mitochondrial oxidative phosphorylation and upregulations of pentose phosphate pathway, glycolysis, and glutaminolysis, leading to tumorigenesis.