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Liver Int. 2019 Jan;39(1):147-157. doi: 10.1111/liv.13957. Epub 2018 Oct 8.

P57-mediated autophagy promotes the efficacy of EGFR inhibitors in hepatocellular carcinoma.

Author information

1
Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.

Abstract

BACKGROUND & AIMS:

Resistance to EGFR-targeted therapy is a major obstacle in hepatocellular carcinoma (HCC) treatment, but its underlying mechanism remains unclear. Autophagy plays a vital role in antitumour treatment. Our previous study suggested that p57 is associated with autophagy and cisplatin resistance. The present study aimed to investigate whether p57 can enhance the sensitivity of HCC cells to Erlotinib (Er)/Cetuximab(C-225) and further explore the potential mechanisms of Er/C-225 resistance.

METHODS:

HCC cells were transfected with pIRES2-EGFP-p57 and pIRES2-EGFP-nc, accompanied by Er/C-225 treatment. Cell viability was detected by an Annexin apoptosis kit and MTT assay. Xenograft experiments were performed to study the function of p57 in the treatment of Er/C-225 in vivo. The level of autophagy was determined by analysis of the appearance of autophagic vacuoles. Western blotting was used to investigate the potential pathways involved.

RESULTS:

Up-regulation of p57 decreased the level of Er/C-225-induced autophagy and enhanced the decrease in Er/C-225-induced cell viability. P57 overexpression combined with CQ treatment further enhanced the therapeutic efficiency of Er/C-225. The xenograft experiment verified that p57 up-regulation sensitizes HCC cells to Er/C-225. Moreover, a mechanistic investigation demonstrated that the up-regulation of p57 resulted in a decrease of LC3B-II and beclin-1, and an increase in p-PI3K, p-AKT and p-mTOR protein expressions.

CONCLUSIONS:

Through activating the PI3K/AKT/mTOR signalling pathway, p57 can reverse Er/C-225-induced autophagy, and thereby increase the therapeutic efficiency of Er/C-225 treatment. Given these results, p57 up-regulation may be applicable as a therapeutic strategy to improve EGFR-targeted therapy in HCC.

KEYWORDS:

EGFR ; P57 ; autophagy; hepatocellular carcinoma

PMID:
30178471
DOI:
10.1111/liv.13957

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