Metabolic reprogramming by PCK1 promotes TCA cataplerosis, oxidative stress and apoptosis in liver cancer cells and suppresses hepatocellular carcinoma

Phosphoenolpyruvate carboxykinase (PEPCK or PCK) catalyzes the first rate-limiting step in hepatic gluconeogenesis pathway to maintain blood glucose levels. Mammalian cells express two PCK genes, encoding for a cytoplasmic (PCPEK-C or PCK1) and a mitochondrial (PEPCK-M or PCK2) isoforms, respectivel...

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Veröffentlicht in:	Oncogene Jg. 37; H. 12; S. 1637 - 1653
Hauptverfasser:	Liu, Meng-Xi, Jin, Lei, Sun, Si-Jia, Liu, Peng, Feng, Xu, Cheng, Zhou-Li, Liu, Wei-Ren, Guan, Kun-Liang, Shi, Ying-Hong, Yuan, Hai-Xin, Xiong, Yue
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	London Nature Publishing Group UK 01.03.2018 Nature Publishing Group
Schlagworte:	101/58 13/1 13/31 14/105 14/63 38/77 42/109 631/67 631/80 64/60 82/51 96/2 Animals Apoptosis Apoptosis - genetics Blood glucose Cancer Cancer cells Cancer genetics Carcinoma Carcinoma, Hepatocellular - genetics Carcinoma, Hepatocellular - metabolism Carcinoma, Hepatocellular - pathology Cell Biology Cell death Cell proliferation Cells (Biology) Cells, Cultured Cellular Reprogramming - genetics Citric Acid Cycle - genetics Colon Energy shortages Gene expression Genes Genes, Tumor Suppressor - physiology Genetic aspects Gluconeogenesis Gluconeogenesis - genetics Glucose HEK293 Cells Hep G2 Cells Hepatocellular carcinoma Hepatocytes Human Genetics Humans Internal Medicine Intracellular Signaling Peptides and Proteins - genetics Intracellular Signaling Peptides and Proteins - physiology Isoforms Ketoglutaric acid Liver cancer Liver Neoplasms - genetics Liver Neoplasms - metabolism Liver Neoplasms - pathology Male Mammalian cells MCF-7 Cells Medicine Medicine & Public Health Metabolism Mice Mice, Inbred ICR Mice, Nude Mitochondria Oncology Oxidative stress Oxidative Stress - genetics Patients Phosphates Phosphoenolpyruvate Carboxykinase (GTP) - genetics Phosphoenolpyruvate Carboxykinase (GTP) - physiology Reactive oxygen species Rodents Skin Therapeutic applications Tumor cell lines Tumorigenesis Tumors
ISSN:	0950-9232, 1476-5594, 1476-5594
Online-Zugang:	Volltext
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Zusammenfassung:	Phosphoenolpyruvate carboxykinase (PEPCK or PCK) catalyzes the first rate-limiting step in hepatic gluconeogenesis pathway to maintain blood glucose levels. Mammalian cells express two PCK genes, encoding for a cytoplasmic (PCPEK-C or PCK1) and a mitochondrial (PEPCK-M or PCK2) isoforms, respectively. Increased expressions of both PCK genes are found in cancer of several organs, including colon, lung, and skin, and linked to increased anabolic metabolism and cell proliferation. Here, we report that the expressions of both PCK1 and PCK2 genes are downregulated in primary hepatocellular carcinoma (HCC) and low PCK expression was associated with poor prognosis in patients with HCC. Forced expression of either PCK1 or PCK2 in liver cancer cell lines results in severe apoptosis under the condition of glucose deprivation and suppressed liver tumorigenesis in mice. Mechanistically, we show that the pro-apoptotic effect of PCK1 requires its catalytic activity. We demonstrate that forced PCK1 expression in glucose-starved liver cancer cells induced TCA cataplerosis, leading to energy crisis and oxidative stress. Replenishing TCA intermediate α-ketoglutarate or inhibition of reactive oxygen species production blocked the cell death caused by PCK expression. Taken together, our data reveal that PCK1 is detrimental to malignant hepatocytes and suggest activating PCK1 expression as a potential treatment strategy for patients with HCC.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	0950-9232 1476-5594 1476-5594
DOI:	10.1038/s41388-017-0070-6