PUM1 knockdown prevents tumor progression by activating the PERK/eIF2/ATF4 signaling pathway in pancreatic adenocarcinoma cells

Autor: Ping Bie, Xingxing Su, Kaicheng Shen, Yishi Yang, Haisu Dai, Ping Zheng, Ling Shuai, Yuan-Deng Luo, Yan Jiang, Zhi-Yu Chen
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
Male
Cancer Research
Epithelial-Mesenchymal Transition
endocrine system diseases
Immunology
Eukaryotic Initiation Factor-2
Apoptosis
Adenocarcinoma
Article
Metastasis
03 medical and health sciences
Cellular and Molecular Neuroscience
Mice
eIF-2 Kinase
0302 clinical medicine
Targeted therapies
Cell Movement
medicine
Animals
Humans
Neoplasm Invasiveness
Neoplasm Metastasis
lcsh:QH573-671
Oncogenesis
Cell Proliferation
Gene knockdown
Oncogene
Chemistry
Cell growth
lcsh:Cytology
RNA-Binding Proteins
Cell Biology
medicine.disease
Activating Transcription Factor 4
digestive system diseases
Gene Expression Regulation
Neoplastic
030104 developmental biology
Tumor progression
030220 oncology & carcinogenesis
Cancer research
Disease Progression
Heterografts
Female
Signal transduction
Carcinoma
Pancreatic Ductal
Signal Transduction
Zdroj: Cell Death and Disease, Vol 10, Iss 8, Pp 1-15 (2019)
Cell Death & Disease
ISSN: 2041-4889
Popis: Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with very poor prognosis. Therefore, it is important to fully understand the molecular mechanism underlying its occurrence and development. Pumilio RNA-binding family member 1 (PUM1) has been reported to function as an oncogene in ovarian cancer and nonsmall cell lung cancer. However, its role and mechanism in PDAC have not been fully illuminated. Here, we found that the PUM1 protein levels were higher in PDAC tissues than in adjacent tissues and that PUM1 levels were significantly associated with TNM stage and overall survival time, indicating a correlation between high PUM1 expression and poor prognosis in patients with PDAC. In vitro and in vivo assays showed that PUM1 knockdown inhibited cell proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT), and promoted apoptosis in MIA PaCa-2 and PANC-1 cells. Through cDNA microarrays and ingenuity pathway analysis, we found that the activation of the eIF2 signaling pathway significantly correlated with PUM1 knockdown. These results were further confirmed by the increased levels of key components of the eIF2 signaling pathway, p-PERK, p-EIF2A, and ATF4 in PUM1 knockdown cells. We also found that PUM1 levels have a significant negative correlation with p-PERK levels in PDAC tissues and that PERK overexpression inhibited cell proliferation, migration, invasion, and EMT, and promoted apoptosis in vitro. Moreover, a PERK inhibitor alleviated the effects of PUM1 knockdown on cell proliferation, apoptosis, migration, invasion, and EMT. Taken together, our results revealed that PUM1 knockdown suppressed cell growth, invasion, and metastasis, and promoted apoptosis by activating the PERK/eIF2/ATF4 signaling pathway in PDAC cells. PUM1 could be a potential target to develop pharmaceuticals and novel therapeutic strategies for the treatment of PDAC.
Databáze: OpenAIRE
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