<p>Knockdown of FOXO6 Inhibits Glycolysis and Reduces Cell Resistance to Paclitaxel in HCC Cells via PI3K/Akt Signaling Pathway</p>

Abstract

Purpose: Previous studies have reported that FOXO6 is highly expressed in hepatocellular carcinoma (HCC) tissues and is associated with the prognosis of HCC patients. However, little research has been carried out to explore the role of FOXO6 in glycolysis of HCC cells and paclitaxel resistance. Today, along with the increasing incidence and mortality of HCC, chemotherapy resistance of HCC also poses a serious challenge. Therefore, this study was set out to investigate the effect of FOXO6 on glycolysis and cytotoxicity of paclitaxel in HCC cells and its potential mechanism. Patients and Methods: The levels of FOXO6 mRNA and protein were detected by qRT-PCR and Western blot, respectively. In addition, paclitaxel-resistant cell lines of HCC cells were established, whose activity was assessed by CCK-8 assay, among which the invasion ability was assessed by Transwell and the apoptosis rate by flow cytometry. What is more, glycolysis levels were evaluated by measuring glucose consumption and lactic acid production, and the protein levels of p-PI3K and p-protein kinase B (Akt) were determined by Western blot. Results: Compared with normal human hepatocytes, FOXO6 was highly expressed in HCC cells, which was of high real value for HCC. FOXO6 knockdown inhibited the proliferation and invasion and induced apoptosis of HCC cells. In addition, FOXO6 knockdown suppressed glycolysis, reversed resistance to chemotherapy in Hep3B/PTX cells and inactivated PI3K and Akt proteins, thus inhibiting the PI3K/Akt signaling pathway. Furthermore, it was found that when activated by 740Y-P, PI3K/Akt signaling pathway could resist the effects of FOXO6 knockdown on the cytotoxicity and glycolysis of paclitaxel in HCC cells. Vice versa, inhibition of PI3K/Akt pathway by LY294002 could resist the effect of FOXO6 overexpression on chemotherapy, cytotoxicity and glycolysis of HCC cells. Conclusion: FOXO6 knockdown can inhibit glycolysis of HCC cells and reduce their resistance to chemotherapy by inhibiting the PI3K/Akt signaling pathway, which may be a new target for the treatment of HCC.

Glycolysis-induced drug resistance in tumors—A response to danger signals?

“…Many of these stimuli lead, directly or indirectly, to the activation of transcription factors that induce the expression of genes encoding glycolytic enzymes. In this regard, the phosphoinositide 3-kinase (PI3K)-AKT-mechanistic target of rapamycin (mTOR) signaling pathway [98 , 103 , 104] as well as the transcription factors hypoxia-inducible factor (HIF)-1α and c-Myc [67 , 94 , 96 , 105] play a prominent, but not exclusive [106] role.…”

“…In most cases, however, the 2 variables may contribute each, to a variable degree, to drug resistance [15 , 51 , 53 , 56 , 97] . In fact, the expression of a particular isoform of a glycolytic enzyme may be linked to the tumorigenic process per se and its overexpression may be the result of intracellular or extracellular stimuli [93] , [94] , [95] , [96] , [97] , [98] , [99] , [100] , [101] , [102] , [103] , [104] , [105] , [106] . Such overexpression would then represent a sufficient condition for setting in motion the molecular mechanisms that ultimately lead to drug resistance.…”

Role of Forkhead Box O Proteins in Hepatocellular Carcinoma Biology and Progression (Review)

“…Previous studies on FOXO6 have primarily focused on the regulation of glucose homeostasis in the liver. However, some studies have demonstrated that FOXO6 serves important roles in the occurrence and development of gastric cancer (40), lung cancer (132), and HCC (15,41,133). Chen et al (41) revealed that FOXO6 is highly expressed in HCC tissue.…”

“…PKB mediates the phosphorylation of FOXO proteins, thereby driving the translocation of FOXO proteins from the nucleus to the cytoplasm, blocking transcriptional activity, and inhibiting transcription. In the cytoplasm, FOXO proteins can dissociate from 14-3-3 proteins and either return to the nucleus or degrade after being ubiquitinated, resulting in persistent suppression of downstream gene expression (12)(13)(14)(15).…”

<p>Emerging Roles and Therapeutic Interventions of Aerobic Glycolysis in Glioma</p>

“…8 In addition, PI3K/Akt, mTOR, and AMPK signalings were also strongly relevant to glycolysis in multiple solid tumors. 9,11 More importantly, the glycolytic process was tightly correlated with various cellular activities, evoking promising therapeutic targets for various tumors. 12,13 For instance, lncRNA maternally expressed gene 3 (MEG3) suppressed proliferation and invasion via regulation of glycolysis in colorectal cancer.…”