ATP Synthase Subunit Epsilon Overexpression Promotes Metastasis by Modulating AMPK Signaling to Induce Epithelial-to-Mesenchymal Transition and Is a Poor Prognostic Marker in Colorectal Cancer Patients

Huang, Yan‐Jiun; Jan, Yi-Hua; Chang, Yu‐Chan; Tsai, Henry J.; Wu, Alexander T.H.; Chen, Chi Long; Hsiao, Michael

doi:10.3390/jcm8071070

Cited by 16 publications

(15 citation statements)

References 41 publications

(59 reference statements)

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“…ATP plays an important role in regulating tumor cell invasion and EMT (Yang et al, 2019). It has been found that extracellular ATP could modulate the MAPK signaling pathway to induce EMT and promote colon cancer cell metastasis (Huang et al, 2019). This study also found that ATP could induce EMT and promoted the metastasis of colon cancer cells.…”

Section: Discussionsupporting

confidence: 54%

Activation of P2×7 Receptor Promotes the Invasion and Migration of Colon Cancer Cells via the STAT3 Signaling

Zhang

Luo

et al. 2020

Front. Cell Dev. Biol.

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The pathological mechanism of colon cancer is very complicated. Therefore, exploring the molecular basis of the pathogenesis of colon cancer and finding a new therapeutic target has become an urgent problem to be solved in the treatment of colon cancer. ATP plays an important role in regulating the progression of tumor cells. P2 × 7 belongs to ATP ion channel receptor, which is involved in the progression of tumors. In this study, we explored the effect and molecular mechanism of ATP-mediated P2 × 7 receptor on the migration and metastasis of colon cancer cells. The results showed that ATP and BzATP significantly increased the inward current and intracellular calcium concentration of LOVO and SW480 cells, while the use of antagonists (A438079 and AZD9056) could reverse the above phenomenon. We found that ATP promoted the migration and invasion of LOVO and SW480 cells and is dose-dependent on ATP concentration (100–300 μM). Similarly, BzATP (10, 50, and 100 μM) also significantly promoted the migration and invasion of colon cancer cells in a concentration-dependent manner. While P2 × 7 receptor antagonists [A438079 (10 μM), AZD9056 (10 μM)] or P2 × 7 siRNA could significantly inhibit ATP-induced colon cancer cell migration and invasion. Moreover, in vivo experiments showed that ATP-induced activation of P2 × 7 receptor promoted the growth of tumors. Furthermore, P2 × 7 receptor activation down-regulated E-cadherin protein expression and up-regulated MMP-2 mRNA and concentration levels. Knocking down the expression of P2 × 7 receptor could significantly inhibit the increase in the expression of N-cadherin, Vimentin, Zeb1, and Snail induced by ATP. In addition, ATP time-dependently induced the activation of STAT3 via the P2 × 7 receptor, and the STAT3 pathway was required for the ATP-mediated invasion and migration. Our conclusion is that ATP-induced P2 × 7 receptor activation promotes the migration and invasion of colon cancer cells, possibly via the activation of STAT3 pathway. Therefore, the P2 × 7 receptor may be a potential target for the treatment of colon cancer.

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Section: Discussionsupporting

confidence: 54%

Activation of P2×7 Receptor Promotes the Invasion and Migration of Colon Cancer Cells via the STAT3 Signaling

Zhang

Luo

et al. 2020

Front. Cell Dev. Biol.

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“…The altered expression of mt-ND2 is critical to multiple disease in human [ 25 , 26 ]. ATP synthase epsilon subunit (ATP5E) gene was found to encode the mitochondrial F0F1 ATP synthase subunit epsilon [ 27 ]. In addition, ATP5E was proven to be required for normal spindle orientation during embryonic divisions in Drosophila [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

The correlated expression of immune and energy metabolism related genes in the response to Salmonella enterica serovar Enteritidis inoculation in chicken

Wang

Miao

et al. 2020

BMC Vet Res

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Background Salmonella enterica serovar Enteritidis (SE) is one of the food-borne pathogenic bacteria, which affects poultry production and poses severe threat to human health. The correlation of immune system and metabolism in chicken after SE inoculation is important but not clear. In the current study, we identified the expression of immune and energy metabolism related genes using quantitative PCR to evaluate the correlation between immune system and energy metabolism against SE inoculation in Jining Bairi chicken. Results ATP5G1, ATP5G3 and ND2 were significantly up-regulated at 1 dpi (day post inoculation), and ATP5E, ATP5G1, ATP5G3 were significantly down-regulated at 7 dpi ( P < 0.05). IL-8 and IL-1 β were significantly down-regulated at 1 dpi, IL-8 and IL-18 were significantly down-regulated at 3 dpi, IL-8 and BCL10 were significantly up-regulated at 7 dpi ( P < 0.05). Conclusions These findings indicate that the correlation between immune and energy metabolism related genes gradually change with time points post SE inoculation, from one homeostasis to an opposite homeostasis with 3 dpi as a turning point. These results will pave the foundation for the relationship between immune system and energy metabolism in the response to SE inoculation in chicken.

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“…Colon cancer cells in which the ε subunit was silenced showed markedly reduced invasive and migratory abilities and ATP5E gene downregulation significantly reduced the incidence of distant metastasis in a mouse xenograft model, suggesting an additional role of the upregulation of some ATP synthase subunits in a more invasive phenotype. In these colon cancer samples the ε subunit level was associated with the AMPK-AKT-HIF1 signalling axis, while its silencing led to the degradation of HIF1α under hypoxia through AMPK-AKT signalling (Huang et al 2019). On the same line, much higher mRNA levels of the OSCP subunit of ATP synthase were detected in a metastatic stomach cancer cell line than in a non-metastatic cancer cell line, that were obtained from the same patient (Salesiotis et al 1995).…”

Section: Expression Of Atp Synthase In Cancermentioning

confidence: 93%

“…Oligomycin treatment prevents differentiation in the HaCaT cell model, which correlates with a decrease in mitochondrial ATP content, supporting the idea that the observed increase in the ATP synthase catalytic subunit has a role in promoting oxidative phosphorylation during HaCaT differentiation. The overexpression of ε subunit encoded by the ATP5E gene was detected in colorectal cancer cells from patients, compared to their normal counterparts ( Figure 2) (Huang et al 2019). Colon cancer cells in which the ε subunit was silenced showed markedly reduced invasive and migratory abilities and ATP5E gene downregulation significantly reduced the incidence of distant metastasis in a mouse xenograft model, suggesting an additional role of the upregulation of some ATP synthase subunits in a more invasive phenotype.…”

Section: Expression Of Atp Synthase In Cancermentioning

confidence: 95%

The role of mitochondrial ATP synthase in cancer

Galber

Acosta

Minervini

et al. 2020

Biological Chemistry

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The mitochondrial ATP synthase is a multi-subunit enzyme complex located in the inner mitochondrial membrane which is essential for oxidative phosphorylation under physiological conditions. In this review, we analyse the enzyme functions involved in cancer progression by dissecting specific conditions in which ATP synthase contributes to cancer development or metastasis. Moreover, we propose the role of ATP synthase in the formation of the permeability transition pore (PTP) as an additional mechanism which controls tumour cell death. We further describe transcriptional and translational modifications of the enzyme subunits and of the inhibitor protein IF1that may promote adaptations leading to cancer metabolism. Finally, we outline ATP synthase gene mutations and epigenetic modifications associated with cancer development or drug resistance, with the aim of highlighting this enzyme complex as a potential novel target for future anti-cancer therapy.

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ATP Synthase Subunit Epsilon Overexpression Promotes Metastasis by Modulating AMPK Signaling to Induce Epithelial-to-Mesenchymal Transition and Is a Poor Prognostic Marker in Colorectal Cancer Patients

Cited by 16 publications

References 41 publications

Activation of P2×7 Receptor Promotes the Invasion and Migration of Colon Cancer Cells via the STAT3 Signaling

Activation of P2×7 Receptor Promotes the Invasion and Migration of Colon Cancer Cells via the STAT3 Signaling

The correlated expression of immune and energy metabolism related genes in the response to Salmonella enterica serovar Enteritidis inoculation in chicken

The role of mitochondrial ATP synthase in cancer

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