Increased lipogenesis in steroid-responsive cancer cells: mechanisms of regulation, role in cancer cell biology and perspectives on clinical applications.
Steroid hormones have a strong influence on the biology of several common human cancers, including cancer of the prostate, breast, endometrium and ovarium. To gain more insight into this process, a screening for androgen-regulated genes was set up in prostate cancer cells. In addition to their well known effects on cell survival, proliferation and differentiated function, androgens were found to markedly stimulate the expression of several lipogenic enzymes. In clinical cancer samples these enzymes are markedly overexpressed in comparison to normal tissues, allowing them to be used as cancer markers and as potential targets for antineoplastic therapy. Investigation of the underlying mechanisms of gene regulation revealed that androgens stimulate lipogenic gene expression through a novel indirect mechanism involving Sterol Regulatory Element-binding Proteins (SREBPs), lipogenic transcription factors that play a key role in the fundamental feedback mechanism of cellular lipid homeostasis. Interestingly, also growth factors, whose signaling pathways are frequently dysregulated and constitutively activated as prostate cancer progresses towards a more advanced disease, stimulate lipogenesis through the same SREBP-mediated mechanism. While studies on the role of enhanced intermediary metabolism in cancer cell biology are progressing, these findings provide important new insights into the long-known dysregulation of intermediary metabolism in cancer cells and open new perspectives for clinical diagnosis and therapeutic intervention.
Swinnen
J V
JV
Laboratory for Experimental Medicine and Endocrinology, Faculty of Medicine-KULeuven U.Z. Gasthuisberg, Onderwijs en Navorsing Herestraat 49-B 3000 Leuven.
D000728:Androgens / Q000378:metabolism*; D015415:Biomarkers; D022762:CCAAT-Enhancer-Binding Proteins / Q000502:physiology; D004268:DNA-Binding Proteins / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D050356:Lipid Metabolism; D008055:Lipids / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors / Q000502:physiology; D014407:Tumor Cells, Cultured
D000728:Androgens; D015415:Biomarkers; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D008055:Lipids; C497387:SREBF1 protein, human; C497390:SREBF2 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors