Rapidly dividing tumor cells require a continuous supply of fatty acids to generate sufficient phospholipids for the stability of their membranes and also for precursors to be used as signaling molecules. It is known that fatty acid synthesis is increased in many tumor types to meet this demand. Fatty acid synthesis begins with palmitic acid and is promoted by the enzyme fatty acid synthase (FAS). The enzyme staroyl-CoA desaturase (SCD-1) then converts palmitic and stearic acids to palmitoleic and oleic acids, respectively. Numerous studies have confirmed that the presence of oleic acid is essential for tumor cell growth. Fatty acid synthesis is under the control of the transcription factor SREBP-1; it regulates the presence of FAS and SCD-1. Brain glioblastoma and lung carcinoma have a high expression of SREBP-1, to support their growth.
SREBP transcription factors collectively regulate the expression of genes for the synthesis of fatty acids and cholesterol. They are initially inactive within the endoplasmic reticulum, anchored to its membrane. They are released by the protease SCAP, which then transports them to the Golgi system for sequential cleavage. This process releases the N-terminal portions of SREBPs, which are free to enter the cell nucleus and activate the transcription of target genes. However, it is not known how SCAP is upregulated in human tumors to promote fat synthesis. Understanding this process could open up new forms of chemotherapy aimed at targeting tumors that depend on lipids for survival. In a new study, scientists at The Ohio State Comprehensive Cancer Center observed that cellular levels of palmitoleic, oleic and other unsaturated acids were lowered by blocking the cellular trasncription factor STAT3.
This protein serves as a proliferative signal transduction factor for many cytokines and growth factors. Researchers found that STAT3 binds directly to the DNA promoter regions of SREBP-1 and SCAP in brain cancer cells. By blocking STAT3 functions with known inhibitors, the composition of cellular phospholipids was significantly altered, as seen by scientists through lipidomic analysis. This is the first study to directly correlate this transcription factor with fat metabolism. Interestingly, another recent study found that STAT3 can regulate the expression of the SREBP-2 isoform to increase cholesterol synthesis in triple-negative breast cancer cells. These data indicate a previously unsuspected role for STAT3 in controlling fat metabolism in normal and cancer cells. Recently, low molecular weight inhibitors of SREBP functions have been synthesized, the most widely used at the laboratory level being fatostatin.
The natural terpenoid betulin (one of the active ingredients in birch sap) and xanthohumol (a bioactive polyphenol found in hops) have also been found to inhibit the SCAP-SREBP-1 cellular pathway and are also being used in the elucidation of this molecular platform. However, none of them have entered clinical practice. Other aggressive and fat-dependent tumors could benefit from drugs of this type, such as prostate and pancreatic cancer. It is likely that when, thanks to the understanding of the underlying molecular mechanisms, enough information is gained, these inhibitors could become mainstream drugs like some current chemotherapeutics (e.g. tyrosine kinase inhibitors) that until twenty years ago were virtually unknown. Today, however, they represent an expanding class that is highly selective in its uses and in the appearance of side effects.
- edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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