# Involvement of the Orexinergic System in Cancer: Antitumor Strategies and Future Perspectives
## 3 Orexins and Cancer
### Hepatocellular Carcinoma  
It has been described that the hepatocellular HepG3B cell line expressed OXR1 mRNA, but not OXR2 mRNA, and that orexin A increased glucose uptake in these cells by promoting pyruvate shunting into the tricarboxylic acid cycle and oxidative phosphorylation, thus decreasing glycolysis [108]. Human hepatocellular samples also expressed OXR1 but not OXR2 [108]. Stress and depression increased the risk of developing liver cancer via the epigenetic downregulation of orexin [109]. The tumor load and the number of liver tumors in depressed rats exposed to chronic unpredictable mild stress were higher than that found in animals without a chronic stimulus [109]. The orexin gene was downregulated in the hippocampi of rats with chronic unpredictable mild stress compared with non-stressed animals, and it has been found that the promoter for orexin was hypermethylated and the orexin mRNA expression downregulated in those animals with depression [109]. Thus, it seems that chronic psychological stressors, through an epigenetic orexin downregulation, play an important role in cancer progression and that this downregulation could be the link between depression and cancer.  
The pharmacogenetic activation of hypothalamic neurons containing orexin or the intracerebral administration of orexin A activated the hepatic mTOR-sXbp1 signaling cascade and attenuated the endoplasmic reticulum stress and inflammation in orexin-deficient mice fed with a high-fat diet; these actions were inhibited with autonomic ganglionic blockers [110]. Moreover, orexin also prevented associated hepatocellularocarcinoma under obesity [110]. Orexin A regulated glucose metabolism through HIF-1\(\alpha\)-independent and -dependent processes in HepG2 human hepatocellular carcinoma cells; in fact, orexin A favored a glucose flux into the mitochondrial oxidative metabolism rather than glycolysis [111]. This study also showed OXR1 in the nuclei of cancer cells, and orexin A favored both mRNA and protein expression of HIF-1\(\alpha\) and its nuclear accumulation; this expression was related to the activation of the PI3K/Akt/mTOR signaling pathway [111]. Orexin A promoted glucose uptake, glucose transporter 1 expression, and ATP generation acting via the HIF-1\(\alpha\) pathway through OXR1 [111]. Orexin A blocked, independently of HIF-1\(\alpha\), lactate production and lactate dehydrogenase/pyruvate dehydrogenase kinase 1 expression and favored pyruvate dehydrogenase B expression and mitochondrial pyruvate dehydrogenase activity [111]. A similar study was performed in the human HepG3B hepatocellular carcinoma cell line; orexin A, through PI3K/Akt/mTOR-dependent and -independent mechanisms, also regulated glucose metabolism in these cells [108]. Thus, orexin A increased glucose uptake and glucose transporter 1 expression, which was associated with the activation of the PI3K/Akt/mTOR pathway, but the peptide also increased the expression of pyruvate dehydrogenase B/mitochondrial pyruvate dehydrogenase activity and decreased lactate dehydrogenase/pyruvate dehydrogenase kinase 1 mRNA levels and lactate generation independently of the PI3K/Akt/mTOR pathway [108]. Thus, orexin A regulates the cellular metabolism towards mitochondrial glucose oxidation rather than glycolysis.