Inhibitory effect of emodin on fatty acid synthase, colon cancer proliferation and apoptosis

Abstract

Fatty acid synthase (FASN) is a key anabolic enzyme for de novo fatty acid synthesis, which is important in the development of colon carcinoma. The high expression of FASN is considered a promising molecular target for colon cancer therapy. Emodin, a naturally occurring anthraquinone, exhibits an anticancer effect in various types of human cancer, including colon cancer; however, the molecular mechanisms remain to be fully elucidated. Cell viability was evaluated using a Cell Counting Kit-8 assay. The apoptosis rate of cells was quantified via flow cytometry following Annexin V/propidium iodide staining. FASN activity was measured by monitoring oxidation of nicotinamide adenine dinucleotide phosphate at a wavelength of 340 nm, and intracellular free fatty acid levels were detected using a Free Fatty Acid Quantification kit. Western blot analysis and reverse transcription-polymerase chain reaction were used to detect target gene and protein expression. The present study was performed to investigate whether the gene expression of FASN and its enzymatic activity are regulated by emodin in a human colon cancer cell line. Emodin markedly inhibited the proliferation of HCT116 cells and a higher protein level of FASN was expressed, compared with that in SW480, SNU-C2A or SNU-C5 cells. Emodin significantly downregulated the protein expression of FASN in HCT116 cells, which was caused by protein degradation due to elevated protein ubiquitination. Emodin also inhibited intracellular FASN enzymatic activity and reduced the levels of intracellular free fatty acids. Emodin enhanced antiproliferation and apoptosis in a dose- and time-dependent manner. The combined treatment of emodin and cerulenin, a commercial FASN inhibitor, had an additive effect on these activities. Palmitate, the final product of the FASN reaction, rescued emodin-induced viability and apoptosis. In addition, emodin altered FASN-involved signaling pathways, including phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinases/extracellular signal-regulated kinases 1/2. These results suggested that emodin-regulated cell growth and apoptosis were mediated by inhibiting FASN and provide a molecular basis for colon cancer therapy.

Emodin induced necroptosis in the glioma cell line U251 via the TNF-α/RIP1/RIP3 pathway

“…Emodin, one of the main effective components in traditional Chinese antitumor herbs [5], has been confirmed to have antitumor activity against many kinds of tumors, such as those in lung cancer [6], breast cancer [7], and colorectal cancer [8]. To date, most studies have demonstrated that emodin has the capability to accelerate apoptosis, induce autophagy, promote cell cycle arrest or inhibit tumor metastasis [9].…”

<p>Fatty acid synthase enhances colorectal cancer cell proliferation and metastasis via regulating AMPK/mTOR pathway</p>

“…Previous studies have described that FASN was overexpressed in CRC and related to disease progression 5,15,16. To further confirm the role of FASN in CRC, we measured the level of FASN protein in 18 randomly selected pairs of CRC tissues and surrounding normal tissues by Western blots.…”

“…Besides, studies showed that overexpression of FASN was associated with tumor cell proliferation, metastasis, poor prognosis and high risk of recurrence 12–14. In CRC, FASN was also shown to be highly expressed and associated with the development and progression of CRC 5,15,16. However, the precise mechanisms of the regulation of cell proliferation and metastasis by FASN are not well understood and remain to be further explored.…”

“…Besides, overexpression of FASN was reported to be associated with tumor cell proliferation, metastasis, poor prognosis and high risk of recurrence 12–14. Recently, there were several studies focusing on FASN in CRC, which described that FASN was overexpressed in CRC and inhibition of FASN blocked the proliferation and metastasis of CRC cells,5,15,16 but the precise underlying mechanisms are equivocal and remain to be further explored.…”

Emodin Induced SREBP1-Dependent and SREBP1-Independent Apoptosis in Hepatocellular Carcinoma Cells

“…We then screened the bioactive components in HSWE and found that emodin (1,3,8-trihydroxy-6-methyl-anthraquinone), a natural anthraquinone derivative, was the major bioactive component (Yang et al, 2018). Studies showed that emodin possessed numerous functions that included arresting cell cycle by blocking cyclin D, cyclin E (Wang et al, 2015), and CDK2 (Zhang et al, 2015); inducing apoptosis by upregulating extrinsic apoptotic fas ligand (FASL) signaling (Li et al, 2014); activating intrinsic apoptotic factors, Cyto c, Caspase-9, and apoptosis-inducing factor (AIF) (Ma et al, 2012); declining the mitochondrial membrane potential (ΔΨm) (Liu et al, 2012); inhibiting migration and invasion by downregulating transforming growth factor-β (TGF-β) (Thacker and Karunagaran, 2015) and Wnt/beta-Catenin signaling pathway (Gu et al, 2019); reversing multidrug resistance by downregulating multidrug resistance-associated protein 1 (MRP1) (Ma et al, 2014), and restricting energy metabolism by inhibiting fatty acid synthase (Lee et al, 2017) in cancers. Moreover, emodin induces both extrinsic and intrinsic apoptosis (Cui et al, 2016).…”