Downregulation of PCK2 remodels tricarboxylic acid cycle in tumor-repopulating cells of melanoma

Luo, Shunqun; Li, Y; Ma, Ru; Liu, J; Xu, Pingwei; Zhang, H; Tang, Ke; Ma, Jia; Liu, N; Zhang, Y; Sun, Yanhong; Ji, Tiantian; Liang, Xiaoyu; Yin, Xiaonan; Liu, Y; Tong, Wei; Niu, Yuqiang; Wang, N; Wang, X; Huang, Bo

doi:10.1038/onc.2016.520

Cited by 52 publications

(53 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Mitochondrial phosphoenolpyruvate carboxykinase (PCK2) is a key enzyme that regulates the carbon flow of the TCA cycle by the conversion of mitochondrial oxaloacetate (OAA) to phosphoenolpyruvate (PEP). Previously, we found that the downregulation of PCK2 leads to increased fumarate levels in B16 melanoma TRCs [38]. Here, we found that PCK2 was highly expressed in normoxic breast cancer TRCs but much lowly expressed under hypoxic conditions (Fig.…”

Section: Pck2 Downregulation Causes Fumarate Accumulation In Hypoxic supporting

confidence: 63%

“…*p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 glycolysis, tricarboxylic acid cycle and gluconeogenesis. Previously, we found that the upregulation of PCK1 but downregulation of PCK2 mediate the retrograde carbon flow to glycerol-3-phosphate for glycerol biogenesis which fixes free fatty acids to lipids in melanoma TRCs [38,47]. Such PCK1-directed carbon retrograde flow has also been found in memory T cells [48].…”

Section: Discussionmentioning

confidence: 84%

See 1 more Smart Citation

Hypoxia-reprogrammed tricarboxylic acid cycle promotes the growth of human breast tumorigenic cells

Tang

Zhu

et al. 2019

Oncogene

View full text Add to dashboard Cite

Clinical applications of antiangiogenic agents profoundly affect tumor cell behaviors via the resultant hypoxia. To date, how the hypoxia regulates tumor cells remains unclear. Here, we show that hypoxia promotes the growth of human breast tumorigenic cells that repopulate tumors [tumor-repopulating cells (TRCs)] in vitro and in vivo. This stimulating effect is ascribed to hypoxia-induced reactive oxygen species (ROS) that activates Akt and NF-κB, dependent on the attenuated tricarboxylic acid (TCA) cycle. We find that fumarate is accumulated in the TCA cycle of hypoxic TRCs, leading to glutathione succination, NADPH/NADP + decrease, and an increase in ROS levels. Mechanistically, hypoxia-increased HIF-1α transcriptionally downregulates the expression of mitochondrial phosphoenolpyruvate carboxykinase (PCK2), leading to TCA cycle attenuation and fumarate accumulation. These findings reveal that hypoxia-reprogrammed TCA cycle promotes human breast TRCs growth via a HIF-1α-downregulated PCK2 pathway, implying a need for a combination of an antiangiogenic therapy with an antioxidant modulator.

show abstract

Section: Pck2 Downregulation Causes Fumarate Accumulation In Hypoxic supporting

confidence: 63%

Section: Discussionmentioning

confidence: 84%

Hypoxia-reprogrammed tricarboxylic acid cycle promotes the growth of human breast tumorigenic cells

Tang

Zhu

et al. 2019

Oncogene

View full text Add to dashboard Cite

show abstract

“…It was recently reported that PCK2 is highly expressed in different cancer cells and samples [ 40 , 41 ]. A recent study also found that PCK2 can regulate TICs in melanoma cells [ 42 ]. However, PCK2 has been found to be downregulated in TICs in melanoma cells and repressed their tumorigenic ability.…”

Section: Discussionmentioning

confidence: 99%

Glycolytic reprogramming through PCK2 regulates tumor initiation of prostate cancer cells

Zhao

Fan

et al. 2017

Oncotarget

View full text Add to dashboard Cite

Tumor-initiating cells (TICs) play important roles in tumor progression and metastasis. Identifying the factors regulating TICs may open new avenues in cancer therapy. Here, we show that TIC-enriched prostate cancer cell clones use more glucose and secrete more lactate than TIC-low clones. We determined that elevated levels of phosphoenolpyruvate carboxykinase isoform 2 (PCK2) are critical for the metabolic switch and the maintenance of TICs in prostate cancer. Information from prostate cancer patient databases revealed that higher PCK2 levels correlated with more aggressive tumors and lower survival rates. PCK2 knockdown resulted in low TIC numbers, increased cytosolic acetyl-CoA and cellular protein acetylation. Our data suggest PCK2 promotes tumor initiation by lowering acetyl-CoA level through reducing the mitochondrial tricarboxylic acid (TCA) cycle. Thus, PCK2 is a potential therapeutic target for aggressive prostate tumors.

show abstract

“…However, PCK2 is a double-edged sword in terms of the occurrence and development of tumors. PCK2 plays an anti-cancer role in HCC and melanoma [35,36], while PCK2 also plays a carcinogenic role in both lung and breast cancer. In the study of HCC, increasing the expression of PCK can lead to energy crisis, truncated gluconeogenesis, TCA cycle rupture and a high ROS level, which can trigger the glucose-deprivation in HCC cells [36].…”

Section: Discussionmentioning

confidence: 99%

Molecular Mechanism of Aflatoxin-Induced Hepatocellular Carcinoma Derived from a Bioinformatics Analysis

Cai

Zheng

She

et al. 2020

Toxins

View full text Add to dashboard Cite

Exposure to aflatoxin is considered to be one of the causes of hepatocellular carcinoma (HCC). With the development of bioinformation, we sought to reveal the occurrence and development of aflatoxin-induced HCC through data research. We identified differentially expressed genes (DEGs) of datasets GSE127791 (Aflatoxin-treated pluripotent stem cell derived human hepatocytes vs. controls) and GSE64041 (liver carcinoma with unknown cause vs. non-cancerous tissue) by GEO2R to find the common DEGs. Gene ontology (GO) and KEGG path enrichment analysis were used to annotate the function of DEGs. Hub genes were screened from identified DEGs by protein-protein interaction (PPI) network analysis. The prognostic value of hub genes in cancer databases were evaluated. We obtained 132 common DEGs and 11 hub genes. According to cluster analysis and protein co-expression networks, we screened out the key genes, histidine-rich glycoprotein (HRG) and phosphoenolpyruvate carboxykinase 2 (PCK2). Oncomine database and survival curve analysis showed that the decline in HRG and PCK2 expression in the development of HCC indicated poor prognosis. We speculated that the decreased expression of HRG and PCK2 after aflatoxin exposure to hepatocyte may be related to aflatoxin induced hepatocyte injury and carcinogenesis. In addition, the decreased expression of HRG and PCK2 in the occurrence and development of HCC suggests a poor prognosis of HCC.

show abstract

Downregulation of PCK2 remodels tricarboxylic acid cycle in tumor-repopulating cells of melanoma

Cited by 52 publications

References 27 publications

Hypoxia-reprogrammed tricarboxylic acid cycle promotes the growth of human breast tumorigenic cells

Hypoxia-reprogrammed tricarboxylic acid cycle promotes the growth of human breast tumorigenic cells

Glycolytic reprogramming through PCK2 regulates tumor initiation of prostate cancer cells

Molecular Mechanism of Aflatoxin-Induced Hepatocellular Carcinoma Derived from a Bioinformatics Analysis

Contact Info

Product

Resources

About