AKT-mediated phosphorylation of ATG4B impairs mitochondrial activity and enhances the Warburg effect in hepatocellular carcinoma cells

Significant ROS production capability of bare iron oxide nanoparticles in safe doses for healthy cells offers an interesting therapeutic window for cancer. In this context, the aim of the current study is to investigate therapeutic potential of the synthesized magnetite (Fe3O4) nanoparticles (~80 nm) as attractive vehicles for biomedical applications on hepatocellular carcinoma cells (HepG2). To investigate their time (0–72 h) and dose (0–100 μg/ml) dependent effect on physiological state (proliferation/ cytotoxicity) and mitochondrial activity of the tumor cells, xCELLigence system and MTT assay were used, respectively. Both 50 and 100 μg/ml of nanoparticle treatment induced significant (p < 0.01) increases in ROS production in HepG2 cells; however, ~4-day real-time cell analysis illustrated that all concentrations of the nanoparticles caused significant (p < 0.01) increases in proliferation of the tumor cells from 4 h after the treatment to the end of the analysis. While 50 and 100 μg/ml of nanoparticles caused significant deteriorations in the mitochondrial activity of the tumor cells in the case of 24 h-(p < 0.05 and p < 0.01, respectively) and 72 h-treatment (p < 0.01); 24 h-treatment of 100 μg/ml of nanoparticles and 72 h-treatment of 50 and 100 μg/ml of nanoparticles caused significant increases in the mitochondrial activity of the tumor cells (p < 0.01) under static magnetic field (1.35 T). Although the synthesized magnetite nanoparticles have not therapeutic potential alone on HepG2 cells in doses safe for healthy cells, the results of the current study are illuminating for future magnetite nanoparticle-based biomedical applications and combination cancer therapy containing magnetite nanoparticles.

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Knockdown of FBI-1 Inhibits the Warburg Effect and Enhances the Sensitivity of Hepatocellular Carcinoma Cells to Molecular Targeted Agents via miR-3692/HIF-1α

Frontiers in Oncology ◽

10.3389/fonc.2021.796839 ◽

2021 ◽

Vol 11 ◽

Author(s):

Juan Liu ◽

Chao Yang ◽

Xiao-Mei Huang ◽

Pan-Pan Lv ◽

Ya-Kun Yang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Warburg Effect ◽

Epithelial Mesenchymal Transition ◽

Carcinoma Cells ◽

Targeted Agents ◽

Related Factors ◽

Mesenchymal Transition ◽

Molecular Targeted Agents ◽

Hcc Cells ◽

The Warburg Effect

The transcription suppressor factor FBI-1 (the factor that binds to inducer of short transcripts-1) is an important regulator of hepatocellular carcinoma (HCC). In this work, the results showed that FBI-1 promoted the Warburg effect and enhances the resistance of hepatocellular carcinoma cells to molecular targeted agents. Knockdown of FBI-1 via its small-interfering RNA (siRNA) inhibited the ATP level, lactate productions, glucose uptake or lactate dehydrogenase (LDH) activation of HCC cells. Transfection of siFBI-1 also decreased the expression of the Warburg-effect-related factors: hypoxia-inducible factor-1 alpha (HIF-1α), lactate dehydrogenase A (LDHA), or GLUT1, and the epithelial–mesenchymal transition-related factors, Vimentin or N-cadherin. The positive correlation between the expression of FBI-1 with HIF-1α, LDHA, or GLUT1 was confirmed in HCC tissues. Mechanistically, the miR-30c repressed the expression of HIF-1α by binding to the 3′-untranslated region (3′-UTR) of HIF-1α in a sequence-specific manner, and FBI-1 enhanced the expression of HIF-1α and HIF-1α pathway’s activation by repressing the expression of miR. By modulating the miR-30c/HIF-1α, FBI-1 promoted the Warburg effect or the epithelial–mesenchymal transition of HCC cells and promoted the resistance of HCC cells to molecular targeted agents.

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