Fatty Acid Synthase Gene Is Up-regulated by Hypoxia via Activation of Akt and Sterol Regulatory Element Binding Protein-1

Abstract

The fatty acid synthase (FAS) gene is significantly up-regulated in various types of cancers, and blocking the FAS expression results in apoptosis of tumor cells. Therefore, FAS is considered to be an attractive target for anticancer therapy. However, the molecular mechanism by which the FAS gene is up-regulated in tumor cells is poorly understood. We found that FAS was significantly up-regulated by hypoxia, which was also accompanied by reactive oxygen species (ROS) generation in human breast cancer cell lines. The FAS expression was also activated by H 2 O 2 , whereas N-acetyl-L-cystein, a ROS inhibitor, suppressed the expression. We also found that the hypoxia significantly up-regulated sterol regulatory-element binding protein (SREBP)-1, the major transcriptional regulator of the FAS gene, via phosphorylation of Akt followed by activation of hypoxia-inducible factor 1 (HIF1). Moreover, our results of reporter assay and chromatin immunoprecipitation analysis indicate that SREBP-1 strongly bound to the SREBP binding site/E-box sequence on the FAS promoter under hypoxia. In our xenograft mouse model, FAS was strongly expressed in the hypoxic regions of the tumor. In addition, our results of immunohistochemical analysis for human breast tumor specimens indicate that the expressions of both FAS and SREBP-1 were colocalized with hypoxic regions in the tumors. Furthermore, we found that hypoxia-induced chemoresistance to cyclophosphamide was partially blocked by a combination of FAS inhibitor and cyclophosphamide. Taken together, our results indicate that FAS gene is up-regulated by hypoxia via activation of the Akt and HIF1 followed by the induction of the SREBP-1 gene, and that hypoxia-induced chemoresistance is partly due to the up-regulation of FAS.

Establishment and characterization of a new hypoxia-resistant cancer cell line, OCUM-12/Hypo, derived from a scirrhous gastric carcinoma

“…The stomach was exposed carefully, and 1.0 Â 10 7 cells were inoculated at the gastric antrum using 30-gauge needles (Handaya, Saitama, Japan). Seven weeks after inoculation, the hypoxic cell marker pimonidazole hydrochloride (Hypoxyprove-1 kit; Chemicon, Temecula, CA, USA) was used to delineate the hypoxic site of the tumours due to its specific binding to cells in a partial oxygen tension o10 mm Hg, as previously reported (Furuta et al, 2008). Pimonidazole (60 mg kg À1 ) was injected to the mouse through tail vein injection 90 min before the animals were killed.…”

Targeting metabolism in breast cancer: How far we can go?

“…PI3k-Akt and the MAPK signal transduction pathway are also thought to be involved in FASN modulation [60,61] . Under hypoxic conditions, FASN gene is upregulated via the activation of Akt followed by the induction of the SREBP-1 gene [62] . Inhibition of MAP kinase also decreases transcription from the FASN promoter and reduces FASN expression in MCF7 cells [63] .…”

Role of Angiotensin Peptides Precursor in Ethanol Mediated Hepato toxicity: Perspective on Angiotensinogen

“…Fatty acid synthase [FAS] gene which is responsible for lipogenesis is upregulated in alcohol exposure as well as in tumor cells which possess hypoxic microenvironments. [88]. The sequence of events of alcohol exposure and its effects are summarized in Table 1.…”