2-Deoxy-D-Glucose Downregulates Fatty Acid Synthase Gene Expression Via an Endoplasmic Reticulum Stress-Dependent Pathway in HeLa Cells
Fatty acid synthase (FASN) catalyzes the rate-limiting step of cellular lipogenesis. FASN expression is upregulated in various types of cancer cells, implying that FASN is a potential target for cancer therapy. 2-Deoxy-D-glucose (2-DG) specifically targets cancer cells by inhibiting glycolysis and g...
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Published in: | Cell biochemistry and biophysics 2024-09, Vol.82 (3), p.2285-2296 |
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Main Authors: | , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites |
Online Access: | Get full text |
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Summary: | Fatty acid synthase (FASN) catalyzes the rate-limiting step of cellular lipogenesis. FASN expression is upregulated in various types of cancer cells, implying that FASN is a potential target for cancer therapy. 2-Deoxy-D-glucose (2-DG) specifically targets cancer cells by inhibiting glycolysis and glucose metabolism, resulting in multiple anticancer effects. However, whether the effects of 2-DG involve lipogenic metabolism remains to be elucidated. We investigated the effect of 2-DG administration on
FASN
expression in HeLa human cervical cancer cells. 2-DG treatment for 24 h decreased FASN mRNA and protein levels and suppressed the activity of an exogenous rat
Fasn
promoter. The use of a chemical activator or inhibitors or of a mammalian expression plasmid showed that neither AMPK nor the Sp1 transcription factor is responsible for the inhibitory effect of 2-DG on
FASN
expression. Administration of thapsigargin, an endoplasmic reticulum (ER) stress inducer, or 4-(2-aminoethyl) benzenesulfonyl fluoride (AEBSF), a site 1 protease inhibitor, mimicked the inhibitory effect of 2-DG on
FASN
expression. 2-DG did not further decrease
FASN
expression in the presence of thapsigargin or AEBSF. Site 1 protease mediates activation of ATF6, an ER stress mediator, as well as sterol regulatory element-binding protein 1 (SREBP1), a robust transcription factor for
FASN
. Administration of 2-DG or thapsigargin for 24 h suppressed activation of ATF6 and SREBP1, as did AEBSF. We speculated that these effects of 2-DG or thapsigargin are due to feedback inhibition via increased GRP78 expression following ER stress. Supporting this, exogenous overexpression of GRP78 in HeLa cells suppressed SREBP1 activation and
Fasn
promoter activity. These results suggest that 2-DG suppresses
FASN
expression via an ER stress-dependent pathway, providing new insight into the molecular basis of FASN regulation in cancer. |
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ISSN: | 1085-9195 1559-0283 1559-0283 |
DOI: | 10.1007/s12013-024-01339-0 |