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Overexpression of P16 reversed the MDR1-mediated DDP resistance in the cervical adenocarcinoma by activating the ERK1/2 signaling pathway

Authors
  • Xiao, Yun1, 2
  • Liang, Mei-rong1, 3
  • Liu, Cheng-cheng3
  • Wang, Ya-nan3
  • Zeng, Yang3
  • Zhou, Jun3
  • Zhu, Hui-ting3
  • Wang, Qin4
  • Zou, Yang5
  • Zeng, Si-yuan1, 3
  • 1 Medical College of Nanchang University, No.461, Bayi Street, Nanchang, Jiangxi, 330006, China , Nanchang (China)
  • 2 Jiangxi Tumor Hospital, Department of Radiotherapy, No. 519, Beijingdong Street, Nanchang, Jiangxi, 330029, China , Nanchang (China)
  • 3 Jiangxi Maternal and Child Health Hospital, Department of Oncology, No. 318, Bayi Street, Nanchang, Jiangxi, 330006, China , Nanchang (China)
  • 4 Duchang Maternal and Child Health Hospital, Department of Obstetrics and Gynecology, No. 79, Dongfeng Street, Duchang, Jiangxi, 332600, China , Duchang (China)
  • 5 Jiangxi Maternal and Child Health Hospital, Center Laboratory, No. 318, Bayi Street, Nanchang, Jiangxi, 330006, China , Nanchang (China)
Type
Published Article
Journal
Cell Division
Publisher
Springer (Biomed Central Ltd.)
Publication Date
Jul 06, 2019
Volume
14
Issue
1
Identifiers
DOI: 10.1186/s13008-019-0048-6
Source
Springer Nature
Keywords
License
Green

Abstract

BackgroundTo investigate the role of P16 (INK4a)-extracellular signal related kinase 1/2 (ERK1/2) signaling pathway in cisplatin (DDP) resistance induced by multidrug resistance protein 1 (MDR1), also known as P-glycoprotein (P-gp), in cervical adenocarcinoma.MethodsA human DDP-resistant HeLa cell line (HeLa/DDP) was constructed using the combination of incremental and intermittent administration of DDP. Cell Counting Kit-8 (CCK-8) assay was used to measure the IC50 and resistance index (RI) of cells. The morphological changes and population doubling time were observed under an inverted microscope. Plate cloning formation assay was performed to evaluate the cell proliferation and tumorigenic ability. Cell invasion and migration were determined by transwell assays. Besides, the expression of P16, phosphorylated extracellular signal related kinase 1 and 2 (pERK1/2), total ERK1/2 and MDR1 were measured using western blot analysis. The ERK-specific inhibitor U0126 and agonist TPA was used to explore the role of ERK.ResultsThe DDP-resistant cervical adenocarcinoma HeLa/DDP cell line was successfully established, which showed stronger cell growth, invasion, and migration. In the HeLa/DDP cells, pERK1/2 was downregulated, P-gp was upregulated and P16 was downregulated. Overexpression of P16 led to a significant decrease in the proliferation rate, migration ability, and invasion ability of the HeLa/DDP cells. Furthermore, overexpression of P16 increased and the decreased expression of pERK1/2 and P-gp in the HeLa/DDP cells, respectively. Treatment of HeLa/DDP cells transfected with P16 plasmid with ERK-specific inhibitor U0126 significantly decreased the expression of pERK1/2 and increased the expression of P-gp from 6 h to 48 h. Moreover, after 72 h, the expression of pERK1/2 was up-regulated and the expression of P-gp was inhibited.ConclusionOverexpression of P16 could partially reverse the MDR1-mediated DDP resistance in the cervical adenocarcinoma by the enhancement of phosphorylation of ERK signaling pathway, which provided a theoretical basis for the treatment of DDP resistance in cervical adenocarcinoma.

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