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Identification of phosphoenolpyruvate carboxykinase 1 as a potential therapeutic target for pancreatic cancer.
- Source :
-
Cell death & disease [Cell Death Dis] 2021 Oct 07; Vol. 12 (10), pp. 918. Date of Electronic Publication: 2021 Oct 07. - Publication Year :
- 2021
-
Abstract
- Pancreatic cancer is the third leading cause of cancer-related mortalities and is characterized by rapid disease progression. Identification of novel therapeutic targets for this devastating disease is important. Phosphoenolpyruvate carboxykinase 1 (PCK1) is the rate-limiting enzyme of gluconeogenesis. The current study tested the expression and potential functions of PCK1 in pancreatic cancer. We show that PCK1 mRNA and protein levels are significantly elevated in human pancreatic cancer tissues and cells. In established and primary pancreatic cancer cells, PCK1 silencing (by shRNA) or CRISPR/Cas9-induced PCK1 knockout potently inhibited cell growth, proliferation, migration and invasion, and induced robust apoptosis activation. Conversely, ectopic overexpression of PCK1 in pancreatic cancer cells accelerated cell proliferation and migration. RNA-seq analyzing of differentially expressed genes (DEGs) in PCK1-silenced pancreatic cancer cells implied that DEGs were enriched in the PI3K-Akt-mTOR cascade. In pancreatic cancer cells, Akt-mTOR activation was largely inhibited by PCK1 shRNA, but was augmented after ectopic PCK1 overexpression. In vivo, the growth of PCK1 shRNA-bearing PANC-1 xenografts was largely inhibited in nude mice. Akt-mTOR activation was suppressed in PCK1 shRNA-expressing PANC-1 xenograft tissues. Collectively, PCK1 is a potential therapeutic target for pancreatic cancer.<br /> (© 2021. The Author(s).)
- Subjects :
- Adult
Aged
Animals
Apoptosis genetics
CRISPR-Cas Systems genetics
Cell Line, Tumor
Cell Movement genetics
Cell Proliferation genetics
Cohort Studies
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Gene Silencing
Humans
Male
Mice, Inbred BALB C
Mice, Nude
Middle Aged
Pancreatic Neoplasms genetics
Pancreatic Neoplasms pathology
Phosphoenolpyruvate Carboxykinase (ATP) genetics
RNA, Messenger genetics
RNA, Messenger metabolism
Signal Transduction
Xenograft Model Antitumor Assays
Mice
Molecular Targeted Therapy
Pancreatic Neoplasms drug therapy
Pancreatic Neoplasms enzymology
Phosphoenolpyruvate Carboxykinase (ATP) metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2041-4889
- Volume :
- 12
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Cell death & disease
- Publication Type :
- Academic Journal
- Accession number :
- 34620839
- Full Text :
- https://doi.org/10.1038/s41419-021-04201-w