Disruption of xCT inhibits cell growth via the ROS/autophagy pathway in hepatocellular carcinoma

Abstract

xCT, the functional subunit of the system $x_c^{-}$ which plays an important role in maintaining intracellular glutathione (GSH) levels, is expressed in various malignant tumors. Here, we demonstrated that xCT expression is often elevated in HCC and is associated with poor prognosis in HCC patients; moreover, disruption of xCT suppressed HCC cell growth both in vitro and in vivo. xCT dysfunction has also been shown to increase intracellular reactive oxygen species (ROS) levels, thus in turn led to autophagic cell death of HCC cells. Taken together, these findings suggest that xCT may be a promising therapeutic target for human HCC.

Introduction

The current literature on nutrient transporters in cancer indicates that tumor cells have a unique metabolic need for nutrients, such as glucose, amino acids, fatty acids, and vitamins, to support the rapid growth of tumor cells [1], [2], [3]. Mammalian cells express a multitude of amino acid transporters [4], [5]. System ${\text{x}}_{\text{c}}^{-}$, consisting of xCT/SLC7A11 and its chaperone CD98/4F2hc (SLC3A2), functions as a Na⁺-independent electroneutral exchange system for cystine/glutamate. Expression of xCT at the cell membrane is essential for the uptake of cystine required for intracellular GSH synthesis. Therefore, xCT plays an important role in maintaining the intracellular redox balance [6], [7]. Mounting evidence has indicated that xCT is expressed in various malignant tumors, such as leukemias, lymphomas, Karposi’s sarcoma, pancreatic cancer [8], [9], and brain cancer [10], [11]. Sulfasalazine (SASP), a potent xCT inhibitor that has been routinely used in the clinical therapy of inflammatory bowel disease and rheumatoid arthritis [12], has been demonstrated to readily result in cystine starvation in a variety of experimental cancers, including lymphoma, prostate, and breast cancer cell lines, which culminated in a growth arrest in vitro and in vivo [13], [14], [15].

Hepatocellular carcinoma (HCC) is one of the most common gastrointestinal malignancies and is the leading cause of cancer-related deaths in East Asia and South Africa [16]. Although xCT, the functional subunit of the system ${\text{x}}_{\text{c}}^{-}$, is expressed in various malignant tumors, its role and implications in hepatocellular carcinoma (HCC) still remain elusive. In this study, we found that the expression of xCT is often upregulated in HCC and is associated with poor prognosis in HCC patients. Importantly, disrupting xCT can inhibit HCC cell growth in vitro and in vivo via the ROS/autophagy pathway in HCC.