A novel positive feedback loop involving FASN/p-ERK1/2/5-LOX/LTB4/FASN sustains high growth of breast cancer cells

Abstract

Aim:To investigate the endogenous signaling pathways associated with high proliferation potential of breast cancer cells. Methods: Breast cancer cell lines LM-MCF-7 and MCF-7 with high and low proliferation capability were used. The promoter activity of fatty acid synthase (FASN) was examined using luciferase reporter gene assay. The expression level of FASN mRNA was measured using RT-PCR and real time PCR, respectively. The level of leukotriene B4 (LTB4) was determined with ELISA. The expression levels of 5-lipoxygenase (5-LOX) was analyzed using RT-PCR and Western blot, respectively. 5-Bromo-20-deoxyuridine (BrdU) incorporation assay was used to study the proliferation of LM-MCF-7 and MCF-7 cells.

The Kaposi's Sarcoma-Associated Herpesvirus (KSHV)-Induced 5-Lipoxygenase-Leukotriene B4 Cascade Plays Key Roles in KSHV Latency, Monocyte Recruitment, and Lipogenesis

“…Wu (80) showed that the induction of fatty acid synthesis and lipogenesis is critical for the survival of KSHV latently infected cells. 5LO is a lipid-metabolizing enzyme (60,81), and LTB4 activates transcription factor NF-B and PPARs, which play significant roles in lipid metabolism and cancer (117). 5LO is an emerging target in obesity, insulin resistance, obesity-related fatty liver disease, metabolic dysfunction (118,119), and nonalcoholic fatty liver and nonalcoholic steatohepatitis (120).…”

“…5LO is an emerging target in obesity, insulin resistance, obesity-related fatty liver disease, metabolic dysfunction (118,119), and nonalcoholic fatty liver and nonalcoholic steatohepatitis (120). Since 5LO/LTB4 has been shown to induce lipogenesis in human sebocytes (121), breast cancer cells (60), and hepatitis B virus X protein-mediated development of hepatocellular carcinoma (122) and since 5LO inhibitors are known to directly downregulate lipogenesis in sebocytes (121) and hepatic steatosis (119), we hypothesized that KSHV infection induces the 5LO/LTB4 cascade to enhance lipogenesis (123,124) and favor latency. Our results show that LTB4 promotes FASN transcription and gene expression and silencing of 5LO effectively reduces the protein levels of FASN (Fig.…”

“…KSHV gene expression has been shown to regulate lipogenesis and support latency (80). FASN, a complex multifunctional enzyme, is a 250-to 270-kDa multifunctional, homodimeric enzyme responsible for energy storage by converting excess carbohydrate to fatty acids that are then sterified to store triacylglycerols (60). 5LO is also known as a lipid-metabolizing enzyme (60,81).…”

“…FASN, a complex multifunctional enzyme, is a 250-to 270-kDa multifunctional, homodimeric enzyme responsible for energy storage by converting excess carbohydrate to fatty acids that are then sterified to store triacylglycerols (60). 5LO is also known as a lipid-metabolizing enzyme (60,81). Its LTB4 metabolite is established to induce transcription factors, such as STAT1, STAT3, NF-B, peroxisome proliferator-activated receptors (PPARs), and early growth response protein 1 (EGR-1), which play significant roles in lipid metabolism and cancer.…”

A remarkable Activity of Steroid Biosynthesis in Captopril Preserved Leydig Cells of Mice Implicated Leukotriene B4 and Gonadotropin Releasing Hormones in vitro

“…The captopril block Ca +2 LTB4 short term period (34) and non-complete LTB4 blocked may be evoked the partially steroidogenic indirectly by deletion activity of MEK1/2 in Leydig cells results in Leydig cells hypoplasia and hypofunction (23). Or presumably through a novel positive local loop involving FASN/p-ERK1/2/5-LOX/LTB4/FASN contributes to the sustaining growth of cells (24).…”