Abstract
Gluconeogenesis, generates glucose from small carbohydrate substrates, and drives the metabolic flux in parallel but opposite to glycolysis. The cytoplasmic isoform of phosphoenolpyruvate carboxykinase (PCK1 or PEPCK-C), a rate-limiting enzyme in gluconeogenesis, initiates the gluconeogenesis process and is reportedly dysregulated in multiple types of cancer. Gluconeogenesis mainly occurs in the liver during fasting, and previous studies have demonstrated that PCK1 acts as a tumor suppressor in hepatocellular carcinoma (HCC); however, the role of PCK1 in cancer progression remains incompletely understood. In the current study, we found that PCK1 expression was decreased in HCC as compared to adjacent normal liver tissues, and low PCK1 expression correlated with poor patient prognosis. Furthermore, overexpression of PCK1 suppressed reactive oxygen species (ROS) production and nuclear translocation of Nrf2 in hepatoma cells. In addition, thioredoxin reductase 1 (TXNRD1), an antioxidant enzyme regulated by the Nrf2/Keap1 pathway, was downregulated upon overexpression of PCK1 in HCC cell lines. Furthermore, we verified this axis using nude mouse xenograft model. Finally, we found that auranofin, a TXNRD1 inhibitor, enhanced the sensitivity of PCK1-knockout hepatoma cells to sorafenib-induced apoptosis. Taken together, our findings suggest that PCK1 deficiency promotes hepatoma cell proliferation via the induction of oxidative stress and the activation of transcription factor Nrf2, and that targeting the TXNRD1 antioxidant pathway sensitizes PCK1-knockout hepatoma cells to sorafenib treatment in vitro.
Highlights
Hepatocellular carcinoma (HCC), the fifth most common cancer worldwide and the third cause of cancer-related mortality [1], is liable to developing malignant and drug-resistant tumors, with high risk of recurrence
These data indicated that PCK1 is generally downregulated in hepatocellular carcinoma (HCC) tissues, which is correlated with poorer prognosis
(24–27) Our results demonstrated that PCK1 was significantly decreased in HCC tumor tissues compared with adjacent normal tissues, which was verified by analysis of data obtained from the The Cancer Genome Atlas (TCGA) database
Summary
Hepatocellular carcinoma (HCC), the fifth most common cancer worldwide and the third cause of cancer-related mortality [1], is liable to developing malignant and drug-resistant tumors, with high risk of recurrence. Tumor cells undergo glycolysis even in the presence of oxygen, known as the “Warburg effect,” which supports tumor growth by accumulating glycolytic intermediates for anabolic biosynthesis [3]. The dysregulation of gluconeogenesis and glycolysis causes a metabolic reprogramming that might be essential for supporting the growth, proliferation, and survival of tumor cells. PCK1, as the first rate-limiting enzyme of gluconeogenesis, catalyzes the conversion of oxaloacetate (OAA) to phosphoenolpyruvate (PEP), and its dysfunction has been related to diabetes, obesity, insulin resistance, fatty liver, and other metabolic diseases [5, 6]. Elevated expression of PCK1 has been reported to benefit tumor growth in certain cancers by maintaining anabolic metabolism [7, 8]. In HCC, PCK1 is downregulated [9], and a functional study indicated that forced PCK1 expression retards hepatoma cell proliferation [10], the underlying mechanism remains to be clarified
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