Article

PKB/Akt induces transcription of enzymes involved in cholesterol and fatty acid biosynthesis via activation of SREBP.

Gene Expression Analysis Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
Oncogene (Impact Factor: 8.56). 10/2005; 24(43):6465-81. DOI: 10.1038/sj.onc.1208802
Source: PubMed

ABSTRACT Protein kinase B (PKB/Akt) has been shown to play a role in protection from apoptosis, cell proliferation and cell growth. It is also involved in mediating the effects of insulin, such as lipogenesis, glucose uptake and conversion of glucose into fatty acids and cholesterol. Sterol-regulatory element binding proteins (SREBPs) are the major transcription factors that regulate genes involved in fatty acid and cholesterol synthesis. It has been postulated that constitutive activation of the phosphatidylinositol 3 kinase/Akt pathway may be involved in fatty acid and cholesterol accumulation that has been described in several tumour types. In this study, we have analysed changes in gene expression in response to Akt activation using DNA microarrays. We identified several enzymes involved in fatty acid and cholesterol synthesis as targets for Akt-regulated transcription. Expression of these enzymes has previously been shown to be regulated by the SREBP family of transcription factors. Activation of Akt induces synthesis of full-length SREBP-1 and SREBP-2 proteins as well as expression of fatty acid synthase (FAS), the key regulatory enzyme in lipid biosynthesis. We also show that Akt leads to the accumulation of nuclear SREBP-1 but not SREBP-2, and that activation of SREBP is required for Akt-induced activation of the FAS promoter. Finally, activation of Akt induces an increase in the concentration of cellular fatty acids as well as phosphoglycerides, the components of cellular membranes. Our data indicate that activation of SREBP by Akt leads to the induction of key enzymes of the cholesterol and fatty acid biosynthesis pathways, and thus membrane lipid biosynthesis.

1 Bookmark
 · 
189 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cancer cells with constitutive phosphatidylinositol 3-kinase (PI3K)/Akt pathway activation have been associated with overexpression of the lipogenic enzyme fatty acid synthase (FAS) as a means to provide lipids necessary for cell growth. In contrast, K-Ras-driven cancer cells suppress utilization of de novo synthesized fatty acids and rely on exogenously supplied fatty acids for cell growth and membrane phospholipid biosynthesis. Consistent with a differential need for de novo fatty acid synthesis, cancer cells with activated PI3K signaling were sensitive to suppression of FAS; whereas mutant K-RAS-driven cancer cells continued to proliferate with suppressed FAS. Surprisingly, in response to FAS suppression, we observed robust increases in both Akt and ERK phosphorylation. Akt phosphorylation was dependent on the insulin-like growth factor-1 receptor (IGF-1R)/PI3K pathway and mTOR complex 2. Intriguingly, K-Ras-mediated ERK activation was dependent on N-Ras. Pharmacological inhibition of PI3K and MEK in K-Ras-driven cancer cells resulted in increased sensitivity to FAS inhibition. These data reveal a surprising sensitivity of K-Ras-driven cancer cells to FAS suppression when stimulation of Akt and Erk was prevented. As K-Ras-driven cancers are notoriously difficult to treat, these findings have therapeutic implications.
    Cancer Letters 07/2014; · 5.02 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cancer development and progression is generally accompanied by significant changes in cel-lular metabolism. Besides an increased flux through glycolysis, a substantial fraction of tu-mors show a marked activation of de novo lipogenesis. This so called "lipogenic switch" op-erates downstream of many common oncogenes and tumor suppressor genes, and involves transcriptional as well as post-transcriptional changes of several enzymes of the lipogenic pathways. In addition to rendering rapidly dividing cells more autonomous in terms of phospholipid and cholesterol supply, activation of de novo lipogenesis evokes a significant shift in membrane phospholipid composition towards more saturated and mono-unsatu-rated acyl species. This shift modulates membrane biophysics, and helps to protect cancer cells from carcinogenesis-and therapy-induced oxidative damage and cell death. Tumor-associated lipogenesis also affects growth factor signaling, and by disturbing the formation of the primary cilium, contributes to impaired environmental sensing, aberrant signal transduction and distorted cell polarization; all hallmarks of cancer. These new insights fuel the concept that alterations in membrane lipid composition play a central role in cancer bi-ology and provide a rationale for the exploration and exploitation of lipogenesis inhibitors as novel antineoplastic agents.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Pten is a tumor suppressor gene regulating many cellular processes, including growth, adhesion, and apoptosis. In the aim of investigating the role of Pten during mammary gland development and lactation of dairy cows, we analyzed Pten expression levels in the mammary glands of dairy cows by using western blotting, immunohistochemistry, and quantitative polymerase chain reaction (qPCR) assays. Dairy cow mammary epithelial cells (DCMECs) were used to study the function of Pten in vitro. We determined concentrations of β-casein, triglyceride, and lactose in the culture medium following Pten overexpression and siRNA inhibition. To determine whether Pten affected DCMEC viability and proliferation, cells were analyzed by CASY-TT and flow cytometry. Genes involved in lactation-related signaling pathways were detected. Pten expression was also assessed by adding prolactin and glucose to cell cultures. When Pten was overexpressed, proliferation of DCMECs and concentrations for β-casein, triglyceride, and lactose were significantly decreased. Overexpression of Pten down-regulated expression of MAPK, CYCLIN D1, AKT, MTOR, S6K1, STAT5, SREBP1, PPARγ, PRLR, and GLUT1, but up-regulated 4EBP1 in DCMECs. The Pten siRNA inhibition experiments revealed results that opposed those from the gene overexpression experiments. Introduction of prolactin (PRL) increased secretion of β-casein, triglyceride, and lactose, but decreased Pten expression levels. Introduction of glucose also increased β-casein and triglyceride concentrations, but did not significantly alter Pten expression levels. The Pten mRNA and protein expression levels were decreased 0.3- and 0.4-fold in mammary glands of lactating cows producing high quality milk (milk protein >3.0%, milk fat >3.5%), compared with those cows producing low quality milk (milk protein <3.0%, milk fat <3.5%). In conclusion, Pten functions as an inhibitor during mammary gland development and lactation in dairy cows. It can down-regulate DCMECs secretion of β-casein, triglyceride, and lactose, and plays a critical role in lactation related signaling pathways.
    PLoS ONE 07/2014; 9(7):e102118. · 3.53 Impact Factor

Full-text (2 Sources)

Download
21 Downloads
Available from
May 21, 2014