Stearoyl‐CoA desaturase‐1 (SCD1) is an endoplasmic reticulum anchored enzyme catalyzing the synthesis of monounsaturated fatty acids, mainly palmytoleyl‐CoA and oleyl‐CoA. Recent studies have revealed a function for SCD1 in the modulation of signaling processes related to cell proliferation, survival and transformation to cancer. We used MCF7 and MDA‐MB‐231 cells to analyze the role of SCD1 in the metastatic acquisition of breast cancer cells. Silencing SCD1 expression in breast cancer cells has no effect on cell viability but the levels of cell proliferation, cell cycle genes' expressions and the phosphorylation state of ERK1/2 MAPK are significantly reduced. Decreasing SCD1 expression also reduces the level of GSK3 phosphorylation, indicating higher activity of the kinase. Using cells fractionation, immunofluorescence and a β‐catenin/TCF‐responsive reporter construct, we demonstrate that lowering SCD1 expression leads to a decrease of β‐catenin amounts within the nucleus and to inhibition of its transactivation capacity. Moreover, MDA‐MB‐231 cells transfected with the SCD1 siRNA show a lower invasive potential than the control cells. Taken together, our data demonstrate that low SCD1 expression is associated with a decrease in the proliferation rate of breast cancer cells associated with a decrease in ERK1/2 activation. SCD1 silencing also inhibits GSK3 phosphorylation, lowering β‐catenin translocation to the nucleus, and, subsequently, its transactivation capacity and the expression of its target genes. Finally, we show that silencing SCD1 impairs the epithelial to mesenchymal transition‐like behavior of the cells, a characteristic of metastatic breast cancer. (Cancer Sci 2013; 104: 36–42)

Stearoyl-CoA desaturase-1 (SCD1) is a key player in lipid metabolism. SCD1 catalyzes the synthesis of monounsaturated fatty acids (MUFA). MUFA are then incorporated into triacylglycerols and phospholipids. Previous studies have shown that Scd1 deficiency in mice induces metabolic changes in the liver characterized by a decrease in de novo lipogenesis and an increase in β-oxidation. Interestingly, Scd1-deficient mice show a decrease in the expression and maturation of the principal lipogenic transcription factor sterol receptor element binding protein-1 (SREBP-1). The mechanisms mediating this effect on de novo lipogenesis and β-oxidation have not been fully elucidated. We evaluated the role of SCD1 on de novo lipogenesis and β-oxidation in HepG2 cells. We also used Scd1-deficient mice and two strains of transgenic mice that produce either oleate (GLS5) or palmitoleate (GLS3) in a liver-specific manner. We demonstrate that the expression of β-oxidation markers increases in SCD1-deficient hepatocytes and suggest that this is due to an increase in cellular polyunsaturated fatty acid content. We also show that the changes in the level of SREBP-1 expression, for both the precursor and the mature forms, are mainly due to the lack of oleate in SCD1-deficient hepatocytes. Indeed, oleate treatment of cultured HepG2 cells or hepatic oleate production in chow-fed GLS5 mice can restore SREBP-1 expression and increase hepatic de novo lipogenesis. Finally, we show that oleate specifically increases SREBP-1 nuclear accumulation, suggesting a central role for oleate in SREBP-1 signaling activity.

De novo lipogenesis (DNL) is now considered as a hallmark of cancer. The overexpression of key enzymes of DNL is characteristic of both primary and advanced disease and may play an important role in resistance to therapies. Here, we showed that DNL is highly enhanced in castrate resistant prostate cancer (CRPC) cells compared to hormone sensitive and enzalutamide resistant cells. This observation suggests that this pathway plays an important role in the initiation of aggressive prostate cancer and in the development of enzalutamide resistance. Importantly, here we show that both prostate cancer cells sensitive and resistant to enzalutamide are dependent on DNL to proliferate. We next combined enzalutamide with an inhibitor of Stearoyl CoA Desaturase 1 (SCD1), an important enzyme in DNL, and observed significantly reduced tumor growth caused by the important change in tumoral lipid desaturation. Our findings suggest that the equilibrium between monounsaturated fatty acids and saturated fatty acids is essential in the establishment of the more aggressive prostate cancer phenotype and that the combination therapy induces a disruption of this equilibrium leading to an important decrease of cell proliferation. These findings provide new insights into the role of DNL in the progression of prostate cancer cells. The study also provides the rationale for the use of an inhibitor of SCD1 in combination with enzalutamide to improve response, delay enzalutamide resistance and improve disease free progression.

Introduction The K-ras proto-oncogene encodes a protein (p21-ras) belonging to the family of GTP/GDP-binding proteins with GTPase activity. The activation of ras family genes plays an important role in colorectal tumorigenesis. Frequency of K-ras mutations and overexpression of the protein in colorectal cancer (CRC) vary between 14% and 50% and between 29% and 76%, respectively. Aims We investigated the clinicopathologic characteristics of patients with CRC and their relationship with point mutations of K-ras oncogene codons 12/13 and ras p21 expression. Materials and Methods K-ras codons 12 and 13 point mutations were examined by direct sequence analysis, whereas the ras p21 expression was evaluated using immunohistochemistry. Results Statistical analysis of immunohistochemical results showed that the expression of ras p21 was correlated with the advanced age of patients (P=0.0001), whereas loss of signal was associated with mucinous histotype (P=0.0001). Mutations in the K-ras gene were detected in 12 of the patients with CRC. Mutations in K-ras gene were found in 12 of 52 tumors (23.07%), and 7 mutations were G→A transitions (58.33% of all mutations), 4 were G→T transversions (33.33%), and only 1 was G→C transversion (8.33%). A total of 83.33% of the mutation occurred at codon 12 and 16.67% at codon 13. Moreover, K-ras mutations were associated with the sex of patients (P=0.017). Conclusions Genetic K-ras alterations were rather low in the Tunisian population, but further study is necessary to unravel the molecular background of CRC.