Knockdown of eukaryotic translation initiation factor 5A2 enhances the therapeutic efficiency of doxorubicin in hepatocellular carcinoma cells by triggering lethal autophagy

Autor: Shangzhi Xie, Xiao-Rui Luan, J. Zhang, Xiaoxiao Zheng, Hai-Ping Ke, Ke Chen, Rong-Rong Liu, Wei Chen, Xian-Ning Zhang, Yuexiao Tang
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
Male
Cancer Research
Cell
chemotherapy
Mice
0302 clinical medicine
Peptide Initiation Factors
Gene knockdown
Liver Neoplasms
RNA-Binding Proteins
Articles
hepatocellular carcinoma
Cell cycle
Middle Aged
Gene Expression Regulation
Neoplastic
medicine.anatomical_structure
Oncology
Liver
autophagic cell death
030220 oncology & carcinogenesis
Gene Knockdown Techniques
Beclin-1
Female
medicine.drug
Signal Transduction
Adult
Programmed cell death
Carcinoma
Hepatocellular
Biology
doxorubicin
eukaryotic translation initiation factor 5A2
03 medical and health sciences
Cell Line
Tumor
medicine
Autophagy
Gene silencing
Animals
Humans
Doxorubicin
Aged
Cell Proliferation
Oncogene
Survival Analysis
Xenograft Model Antitumor Assays
digestive system diseases
030104 developmental biology
Drug Resistance
Neoplasm
Cancer research
Zdroj: International Journal of Oncology
ISSN: 1791-2423
1019-6439
Popis: Hepatocellular carcinoma (HCC) is an invasive malignant neoplasm with a poor prognosis. The development of chemoresistance severely obstructs the chemotherapeutic efficiency of HCC treatment. Therefore, understanding the mechanisms of chemoresistance is important for improving the outcomes of patients with HCC. Eukaryotic translation initiation factor 5A2 (eIF5A2), which is considered to be an oncogene, has been reported to mediate chemoresistance in various types of cancer; however, its precise role in HCC remains unclear. Accumulating evidence has suggested that autophagy serves a dual role in cancer chemotherapy. The present study aimed to investigate the role of autophagy in eIF5A2-mediated doxorubicin resistance in HCC. High expression levels of eIF5A2 in human HCC tissues were observed by immunohistochemistry using a tissue microarray, which was consistent with the results of reverse transcription-quantitative PCR analysis in paired HCC and adjacent healthy tissues. HCC patient-derived tumor xenograft mouse model was used for the in vivo study, and knockdown of eIF5A2 effectively enhanced the efficacy of doxorubicin chemotherapy compared with that in the control group. Notably, eIF5A2 served as a repressor in regulating autophagy under chemotherapy. Silencing of eIF5A2 induced doxorubicin sensitivity in HCC cells by triggering lethal autophagy. In addition, 5-ethynyl-2′-deoxyuridine, lactate dehydrogenase release assay and calcein-AM/PI staining were used to determine the enhanced autophagic cell death induced by the silencing of eIF5A2 under doxorubicin treatment. Suppression of autophagy attenuated the sensitivity of HCC cells to doxorubicin induced by eIF5A2 silencing. The results also demonstrated that knockdown of the Beclin 1 gene, which is an autophagy regulator, reversed the enhanced autophagic cell death and doxorubicin sensitivity induced by eIF5A2 silencing. Taken together, these results suggested eIF5A2 may mediate the chemoresistance of HCC cells by suppressing autophagic cell death under chemotherapy through a Beclin 1-dependent pathway, and that eIF5A2 may be a novel potential therapeutic target for HCC treatment.
Databáze: OpenAIRE
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