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

Long-term sorafenib treatment triggers resistance to chemotherapy in patients with hepatocellular carcinoma (HCC). In order to investigate the mechanisms of sorafenib resistance in HCC, the aim of the present study was to develop a resistant human liver cell line via long-term exposure to sorafenib....

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Bibliographic Details
Published in:Oncology letters 2018-06, Vol.15 (6), p.9377-9384
Main Authors: Zhang, Hao, Wang, Qingqing, Liu, Jun, Cao, Haoqiang
Format: Article
Language:English
Subjects:
Biotechnology
Care and treatment
Cellular signal transduction
Development and progression
Drug resistance
Drug therapy
Growth factors
Health aspects
Hepatocellular carcinoma
Immunoglobulins
Inhibitor drugs
Kinases
Laboratories
Liver cancer
Metastasis
Oncology
Patient outcomes
Polymerase chain reaction
Prevention
Proteins
Signal transduction
Sorafenib
Studies
Targeted cancer therapy
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Summary:Long-term sorafenib treatment triggers resistance to chemotherapy in patients with hepatocellular carcinoma (HCC). In order to investigate the mechanisms of sorafenib resistance in HCC, the aim of the present study was to develop a resistant human liver cell line via long-term exposure to sorafenib. The cytotoxicity cell counting kit-8 assay was used to evaluate drug sensitivity. Reverse transcription-quantitative polymerase chain reaction and western blotting were used to examine the molecular mechanisms underpinning sorafenib resistance. Migratory and invasive properties in resistant cells were assessed using Transwell assays. The results from the present study revealed that resistant cells became insensitive to sorafenib treatment and exhibited increased migratory and invasive capacities. Activation of the phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway and epithelial-mesenchymal transition was characteristic of resistant cells. The use of LY294002, a PI3K inhibitor, was able to suppress the activation of Akt and extracellular signal-regulated kinase 1/2, attenuated the migratory and invasive capacities of resistant cells. Data from the present study indicates that inhibition of the PI3K signaling pathway with LY294002 exerts suppressive effects on sorafenib resistance and provides an attractive novel therapeutic regime in patients with advanced HCC.
ISSN:1792-1074
1792-1082
DOI:10.3892/ol.2018.8536