Abrogation of de novo lipogenesis by stearoyl-CoA desaturase 1 inhibition interferes with oncogenic signaling and blocks prostate cancer progression in mice.
Increased de novo fatty acid (FA) synthesis is one hallmark of tumor cells, including prostate cancer. We present here our most recent results showing that lipid composition in human prostate cancer is characterized by an increased ratio of monounsaturated FA to saturated FA, compared with normal prostate, and evidence the overexpression of the lipogenic enzyme stearoyl-CoA desaturase 1 (SCD1) in human prostate cancer. As a new therapeutic strategy, we show that pharmacologic inhibition of SCD1 activity impairs lipid synthesis and results in decreased proliferation of both androgen-sensitive and androgen-resistant prostate cancer cells, abrogates the growth of prostate tumor xenografts in nude mice, and confers therapeutic benefit on animal survival. We show that these changes in lipid synthesis are translated into the inhibition of the AKT pathway and that the decrease in concentration of phosphatidylinositol-3,4,5-trisphosphate might at least partially mediate this effect. Inhibition of SCD1 also promotes the activation of AMP-activated kinase and glycogen synthase kinase 3alpha/beta, the latter on being consistent with a decrease in beta-catenin activity and mRNA levels of various beta-catenin growth-promoting transcriptional targets. Furthermore, we show that SCD1 activity is required for cell transformation by Ras oncogene. Together, our data support for the first time the concept of targeting the lipogenic enzyme SCD1 as a new promising therapeutic approach to block oncogenesis and prostate cancer progression.
Fritz
Vanessa
V
Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.
Benfodda
Zohra
Z
Rodier
Geneviève
G
Henriquet
Corinne
C
Iborra
François
F
Avancès
Christophe
C
Allory
Yves
Y
de la Taille
Alexandre
A
Culine
Stéphane
S
Blancou
Hubert
H
Cristol
Jean Paul
JP
Michel
Françoise
F
Sardet
Claude
C
Fajas
Lluis
L
D000818:Animals; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology; D006801:Humans; D050155:Lipogenesis / Q000187:drug effects; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects*; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D004791:Enzyme Inhibitors; D005229:Fatty Acids, Monounsaturated; D016159:Tumor Suppressor Protein p53; D013230:Stearoyl-CoA Desaturase