Activation of phosphatidylinositol 3-kinase/AKT/snail signaling pathway contributes to epithelial-mesenchymal transition-induced multi-drug resistance to sorafenib in hepatocellular carcinoma cells

Abstract

Sorafenib, an orally available kinase inhibitor, is the standard first-line systemic drug for advanced hepatocellular carcinoma (HCC), and it exerts potent inhibitory activity against epithelial–mesenchymal transition (EMT) and multidrug resistance (MDR) by inhibiting mitogen-activated protein kinase (MAPK) signaling in HCC. However, after long-term exposure to sorafenib, HCC cells exhibit EMT and resistance to sorafenib. The activation of AKT by sorafenib is thought to be responsible for the development of these characteristics. The present study aims to examine the underlying mechanism and seek potential strategies to reverse this resistance and the progression to EMT. Sorafenib-resistant cells showed increased metastatic and invasive ability, with a higher expression of P-glycoprotein (P-gp), compared with the parental cells. This phenomenon was at least partially due to EMT and the appearance of MDR in sorafenib-resistant HCC cells. Moreover, MDR was a downstream molecular event of EMT. Silencing Snail with siRNA blocked EMT and partially reversed the MDR, thereby markedly abolishing invasion and metastasis in sorafenib-resistant HCC cells, but silencing of MDR1 had no effect on the EMT phenotype. Additionally, HCC parental cells that were stably transfected with pCDNA3.1-Snail exhibited EMT and MDR. Two sorafenib-resistant HCC cell lines, established from human HCC HepG2 and Huh7 cells, were refractory to sorafenib-induced growth inhibition but were sensitive to MK-2206, a novel allosteric AKT inhibitor. Thus, the combination of sorafenib and MK-2206 led to significant reversion of the EMT phenotype and P-gp-mediated MDR by downregulating phosphorylated AKT. These findings underscore the significance of EMT, MDR and enhanced PI3K/AKT signaling in sorafenib-resistant HCC cells.

Inhibition of the PI3K/Akt signaling pathway reverses sorafenib‑derived chemo‑resistance in hepatocellular carcinoma

“…Multiple studies have reported that the activation of the PI3K/Akt signaling pathway induces chemoresistance in HCC cells (18)(19)(20). Meanwhile, the MAPK signaling pathway is a major target of sorafenib therapy.…”

Characterization of Factors Involved in Localized Translation Near Mitochondria by Ribosome-Proximity Labeling

“…HEK-293T1 cells were seeded in a medium depleted of biotin 24 h before transfection with 10 µg TOM20-mVenus-BirA plasmid per 100 mm plate and grown for another 24 h in biotin-depleted medium before harvest. For siRNA treatments, cells were grown to 50% confluence in biotin-containing media and transfected with siRNA against human Tom70 (Dharmacon M02124301) , human CLUH (Invitrogen 1299003) (Gao et al, 2014) or control irrelevant siRNA (Sense 5 -UUCUCCGAACGUGUCACGU-3 ) (Dong et al, 2017) in a final concentration of 100 nM. At this stage, growth was shifted to a biotin-depleted medium.…”

Restraining Network Response to Targeted Cancer Therapies Improves Efficacy and Reduces Cellular Resistance

“…To establish potential translational relevance of our findings, we surveyed previous studies of molecular mechanisms of sorafenib resistance in human tumors. We found that indeed the InsR/IGF (26,27), EGFR (28,29), Akt (30,31), Src kinases (32), and multiple RTK's (29) were all pathways contributing to sorafenib resistance in human cancer cells. In our Drosophila studies restraining these pathways in normal and transformed cells, either genetically or pharmacologically, correlated with increased sorafenib efficacy ( Fig.…”