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Stabilization of LKB1 and Akt by neddylation regulates energy metabolism in liver cancer.

Barbier-Torres L, Delgado TC, García-Rodríguez JL, Zubiete-Franco I, Fernández-Ramos D, Buqué X, Cano A, Gutiérrez-de Juan V, Fernández-Domínguez I, Lopitz-Otsoa F, Fernández-Tussy P, Boix L, Bruix J, Villa E, Castro A, Lu SC, Aspichueta P, Xirodimas D, Varela-Rey M, Mato JM, Beraza N, Martínez-Chantar ML - Oncotarget (2015)

Bottom Line: Tumor cell death in vivo translating into liver tumor regression was associated with augmented phosphatidylcholine synthesis by the PEMT pathway, known as a liver-specific tumor suppressor, and restored mitochondrial function and TCA cycle flux.Otherwise, in protumoral hepatocytes, neddylation inhibition resulted in metabolic reprogramming rendering a decrease in oxidative phosphorylation and concomitant tumor cell apoptosis.Importantly, we show that neddylation-induced metabolic reprogramming and apoptosis were dependent on LKB1 and Akt stabilization.

View Article: PubMed Central - PubMed

Affiliation: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Bizkaia Science and Technology Park, Derio, Bizkaia, Spain.

ABSTRACT
The current view of cancer progression highlights that cancer cells must undergo through a post-translational regulation and metabolic reprogramming to progress in an unfriendly environment. In here, the importance of neddylation modification in liver cancer was investigated. We found that hepatic neddylation was specifically enriched in liver cancer patients with bad prognosis. In addition, the treatment with the neddylation inhibitor MLN4924 in Phb1-KO mice, an animal model of hepatocellular carcinoma showing elevated neddylation, reverted the malignant phenotype. Tumor cell death in vivo translating into liver tumor regression was associated with augmented phosphatidylcholine synthesis by the PEMT pathway, known as a liver-specific tumor suppressor, and restored mitochondrial function and TCA cycle flux. Otherwise, in protumoral hepatocytes, neddylation inhibition resulted in metabolic reprogramming rendering a decrease in oxidative phosphorylation and concomitant tumor cell apoptosis. Moreover, Akt and LKB1, hallmarks of proliferative metabolism, were altered in liver cancer being new targets of neddylation. Importantly, we show that neddylation-induced metabolic reprogramming and apoptosis were dependent on LKB1 and Akt stabilization. Overall, our results implicate neddylation/signaling/metabolism, partly mediated by LKB1 and Akt, in the development of liver cancer, paving the way for novel therapeutic approaches targeting neddylation in hepatocellular carcinoma.

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Association between LKB1, Akt and neddylation in human HCC(A) LKB1 and Akt IHC analysis in human samples from normal liver (NL) and HCC human samples from patients with good and bad prognosis. Graphical representations are shown on the right of each panel. (B) LKB1 and Akt mRNA expression in human samples from patients with HCC with good or bad prognosis. (C) Pearson's correlation between neddylation and LKB1 or Akt levels respectively. (D) ROC curves of LKB1 and Akt in good and bad prognosis of human HCC samples. The area under the ROC curve (AUC) measures the statistical potential of Akt and LKB1 to differentiate the two prognosis groups. Values are represented as mean ± SEM. *p<0.05 (Bad vs good prognosis).
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Figure 4: Association between LKB1, Akt and neddylation in human HCC(A) LKB1 and Akt IHC analysis in human samples from normal liver (NL) and HCC human samples from patients with good and bad prognosis. Graphical representations are shown on the right of each panel. (B) LKB1 and Akt mRNA expression in human samples from patients with HCC with good or bad prognosis. (C) Pearson's correlation between neddylation and LKB1 or Akt levels respectively. (D) ROC curves of LKB1 and Akt in good and bad prognosis of human HCC samples. The area under the ROC curve (AUC) measures the statistical potential of Akt and LKB1 to differentiate the two prognosis groups. Values are represented as mean ± SEM. *p<0.05 (Bad vs good prognosis).

Mentions: Many of the oncogenic drivers observed in cancer alter tumor-metabolism as part of their mode of action. LKB1 and Akt are well known metabolism regulators in healthy liver. However, the activity of both kinases has been associated with HCC development [11-14]. Importantly, IHC and Western blot analysis showed that LKB1 and Akt levels were considerably overexpressed in HCC patients, being further increased in those with poor outcome prognosis (Fig. 4A). Whereas increased protein levels of LKB1 are associated with the transcriptional upregulation of STK11 (the gene encoding for LKB1), the same is not valid for Akt (Fig. 4B).


Stabilization of LKB1 and Akt by neddylation regulates energy metabolism in liver cancer.

Barbier-Torres L, Delgado TC, García-Rodríguez JL, Zubiete-Franco I, Fernández-Ramos D, Buqué X, Cano A, Gutiérrez-de Juan V, Fernández-Domínguez I, Lopitz-Otsoa F, Fernández-Tussy P, Boix L, Bruix J, Villa E, Castro A, Lu SC, Aspichueta P, Xirodimas D, Varela-Rey M, Mato JM, Beraza N, Martínez-Chantar ML - Oncotarget (2015)

Association between LKB1, Akt and neddylation in human HCC(A) LKB1 and Akt IHC analysis in human samples from normal liver (NL) and HCC human samples from patients with good and bad prognosis. Graphical representations are shown on the right of each panel. (B) LKB1 and Akt mRNA expression in human samples from patients with HCC with good or bad prognosis. (C) Pearson's correlation between neddylation and LKB1 or Akt levels respectively. (D) ROC curves of LKB1 and Akt in good and bad prognosis of human HCC samples. The area under the ROC curve (AUC) measures the statistical potential of Akt and LKB1 to differentiate the two prognosis groups. Values are represented as mean ± SEM. *p<0.05 (Bad vs good prognosis).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4385867&req=5

Figure 4: Association between LKB1, Akt and neddylation in human HCC(A) LKB1 and Akt IHC analysis in human samples from normal liver (NL) and HCC human samples from patients with good and bad prognosis. Graphical representations are shown on the right of each panel. (B) LKB1 and Akt mRNA expression in human samples from patients with HCC with good or bad prognosis. (C) Pearson's correlation between neddylation and LKB1 or Akt levels respectively. (D) ROC curves of LKB1 and Akt in good and bad prognosis of human HCC samples. The area under the ROC curve (AUC) measures the statistical potential of Akt and LKB1 to differentiate the two prognosis groups. Values are represented as mean ± SEM. *p<0.05 (Bad vs good prognosis).
Mentions: Many of the oncogenic drivers observed in cancer alter tumor-metabolism as part of their mode of action. LKB1 and Akt are well known metabolism regulators in healthy liver. However, the activity of both kinases has been associated with HCC development [11-14]. Importantly, IHC and Western blot analysis showed that LKB1 and Akt levels were considerably overexpressed in HCC patients, being further increased in those with poor outcome prognosis (Fig. 4A). Whereas increased protein levels of LKB1 are associated with the transcriptional upregulation of STK11 (the gene encoding for LKB1), the same is not valid for Akt (Fig. 4B).

Bottom Line: Tumor cell death in vivo translating into liver tumor regression was associated with augmented phosphatidylcholine synthesis by the PEMT pathway, known as a liver-specific tumor suppressor, and restored mitochondrial function and TCA cycle flux.Otherwise, in protumoral hepatocytes, neddylation inhibition resulted in metabolic reprogramming rendering a decrease in oxidative phosphorylation and concomitant tumor cell apoptosis.Importantly, we show that neddylation-induced metabolic reprogramming and apoptosis were dependent on LKB1 and Akt stabilization.

View Article: PubMed Central - PubMed

Affiliation: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Bizkaia Science and Technology Park, Derio, Bizkaia, Spain.

ABSTRACT
The current view of cancer progression highlights that cancer cells must undergo through a post-translational regulation and metabolic reprogramming to progress in an unfriendly environment. In here, the importance of neddylation modification in liver cancer was investigated. We found that hepatic neddylation was specifically enriched in liver cancer patients with bad prognosis. In addition, the treatment with the neddylation inhibitor MLN4924 in Phb1-KO mice, an animal model of hepatocellular carcinoma showing elevated neddylation, reverted the malignant phenotype. Tumor cell death in vivo translating into liver tumor regression was associated with augmented phosphatidylcholine synthesis by the PEMT pathway, known as a liver-specific tumor suppressor, and restored mitochondrial function and TCA cycle flux. Otherwise, in protumoral hepatocytes, neddylation inhibition resulted in metabolic reprogramming rendering a decrease in oxidative phosphorylation and concomitant tumor cell apoptosis. Moreover, Akt and LKB1, hallmarks of proliferative metabolism, were altered in liver cancer being new targets of neddylation. Importantly, we show that neddylation-induced metabolic reprogramming and apoptosis were dependent on LKB1 and Akt stabilization. Overall, our results implicate neddylation/signaling/metabolism, partly mediated by LKB1 and Akt, in the development of liver cancer, paving the way for novel therapeutic approaches targeting neddylation in hepatocellular carcinoma.

Show MeSH
Related in: MedlinePlus