Author(s): Menendez JA, Colomer R, Lupu R
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Abstract The hyperactivation of fatty acid synthase (FAS)-catalyzed de novo biosynthesis of fatty acids is a molecular marker linked to tumor virulence in population studies of human malignancies. This activation appears to be linked to neoplastic transformation, since high levels of FAS have also been identified in pre-malignant lesions. This dependence of cancer upon accelerated lipogenesis differs from normal human tissues, in which FAS is suppressed by the presence of small amounts of fatty acids in the diet. The molecular mechanisms by which cancer cells constitutively exhibit FAS overexpression and hyperactivity have begun to emerge. The active involvement of the mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase (MAPK ERK1/2) and phosphatidylinositol-3'-kinase (PI-3'K)/protein kinase B (AKT) transduction cascades in the overexpression of FAS has been recently demonstrated in several cancer cell models. Strikingly, insulin-regulated stimulation of FAS expression in adipose cells is also mediated by the PI-3'K pathway with AKT being involved as a downstream effector. Moreover, FAS overexpression in tumor cells has been demonstrated to occur through a modification of the transcription factor sterol regulatory element-binding protein-1c (SREBP-1c), the major regulatory factor of FAS in liver and adipose tissues, which, in turn, is known to be regulated by MAPK ERK1/2 and PI-3'K/AKT pathways. Therefore, the signal transduction pathways regulating FAS expression in normal and cancer cells seem to share several downstream elements. However, the upstream mechanisms controlling FAS expression in cancer cells must be different from those in normal tissues, since tumor-associated FAS expression seems to be insensitive to nutritional signals. In pre-neoplastic lesions, we hypothesize that the early activation of FAS in pre-malignant cells represents a survival strategy which occurs to compensate for an insufficiency of both oxygen and dietary fatty acids due to, e.g., lack of angiogenesis. Thus, FAS activation reflects an epigenetic dysregulation of the lipogenic pathway in response to the microenvironment of tumors containing regions of poor oxygenation. Upon this unusual metabolic situation, FAS up-regulation also represent a metabolic strategy to maintain high proliferation rates of surviving cells in the absence of exogenous dietary fatty acids. Concomitantly, a variety of oncogenic changes (H-ras, erb B-2, etc.) may result in the constitutive activation of MAPK and PI-3'K/AKT signaling cascades, which, in turn, can activate SREBP-1c and, subsequently, tumor-associated FAS-catalyzed endogenous lipogenesis. Thereafter, high levels of FAS are maintained in coordination with increased demand for fatty acid metabolism and/or membrane synthesis in response to cancer-related overexpression of growth factors (e.g., EGF, heregulin) and/or growth factor receptors (e.g., EGFR, Her-2/neu). The aberrant MAPK and PI-3'K/AKT cascades driven by these oncogenic changes subvert the downregulatory effects of physiological concentrations of dietary fatty acids, resulting in a cancer-associated FAS insensitivity to nutritional signals. This model does not exclude that fundamental differences in the ability of FAS gene to respond to normal fatty acid's downregulatory actions may also synergistically interact with oncogenic signals to constitutively maintain an elevated FAS-dependent de novo endogenous fatty acid biogenesis in cancer cells in spite of high levels of circulating dietary fatty acids.
This article was published in Med Hypotheses
and referenced in Journal of Glycomics & Lipidomics