Enhanced antitumor activity of cerulenin combined with oxaliplatin in human colon cancer cells

Shiragami, Risa; Murata, Soichiro; Kosugi, Chihiro; Tezuka, Tohru; Yamazaki, Masato; Hirano, Atsushi; Yoshimura, Yuichiro; Suzuki, Masato; Shuto, Kiyohiko; Koda, Keiji

doi:10.3892/ijo.2013.1978

Cited by 67 publications

(55 citation statements)

References 28 publications

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“…It has been suggested that inhibiting FASN pharmacologically reduces cell growth and survival, and induces the apoptosis of colon cancer cells (34). For example, cerulenin, a natural FASN inhibitor, enhances antitumor activity when combined with oxaliplatin in human colon cancer cells (35) and suppresses liver metastasis of colon cancer (36). C75, a stable synthetic small molecule developed specifically for inhibiting FASN, produces a cytotoxic effect modulated by p53 in colon carcinoma cells (37).…”

Section: Discussionmentioning

confidence: 99%

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

Lee

Young

et al. 2017

Molecular Medicine Reports

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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.

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Section: Discussionmentioning

confidence: 99%

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

Lee

Young

et al. 2017

Molecular Medicine Reports

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“…12 Inversely, downregulation of AKT signaling reduces the dose of L-OHP and is considered to endure the chemotherapy. 13 Some genes are known to regulate AKT pathway nowadays. For instance, erb-b2 receptor tyrosine kinase 4 (ERBB4) is acknowledged to upregulate the activation of AKT signaling.…”

Section: Introductionmentioning

confidence: 99%

Linc00152 Functions as a Competing Endogenous RNA to Confer Oxaliplatin Resistance and Holds Prognostic Values in Colon Cancer

et al. 2016

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Long noncoding RNAs act as crucial regulators in plenty of human cancers, yet their potential roles and molecular mechanisms in chemoresistance are poorly understood. This study showed that a novel lncRNA, long intergenic noncoding RNA 152 (Linc00152 ), promoted tumor progression and conferred resistance to oxaliplatin (L-OHP)-induced apoptosis in vitro and in vivo. It antagonized chemosensitivity through acting as a competing endogenous RNA to modulate the expression of miR-193a-3p, and then erb-b2 receptor tyrosine kinase 4 (ERBB4). Knockdown of ERBB4 in colon cancer cells decreased AKT phosphorylation, which resulted in decreased L-OHP resistance. Consistent with above findings, the specific AKT signaling inhibitor and activator were used, respectively, which demonstrated that Linc00152 contributed to L-OHP resistance at least partly through activating AKT pathway. Further studies indicated that Linc00152 was increased and appeared to be an independent prognostic factor for decreased survival and increased disease recurrence in stage II and III colon cancer patients undergoing L-OHP-based chemotherapy after surgery. Collectively, our findings established Linc00152 as a candidate prognostic indicator of outcome and drug responsiveness in colon cancer patients, and the involvement of competing endogenous RNAs mechanism in Linc00152/ miR-193a-3p/ERBB4/AKT signaling axis may provide a novel choice in the investigation of drug resistance.

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“…Together with our recent reports on regulation of AKT by cPLA 2 α and its enzymatic products [20], these findings suggest the presence of feed-forward loop between AKT and lipid modifying enzymes that favours cancer cell proliferation. Not surprisingly, it has been suggested that chemotherapy targeting both AKT signaling and lipid metabolism might be of benefit [39, 40]. …”

Section: Discussionmentioning

confidence: 99%

Loss of PTEN stabilizes the lipid modifying enzyme cytosolic phospholipase A2α via AKT in prostate cancer cells

Vignarajan

Xie

et al. 2014

Oncotarget

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Aberrant increase in pAKT, due to a gain-of-function mutation of PI3K or loss-of-function mutation or deletion of PTEN, occurs in prostate cancer and is associated with poor patient prognosis. Cytosolic phospholipase A2α (cPLA2α) is a lipid modifying enzyme by catalyzing the hydrolysis of membrane arachidonic acid. Arachidonic acid and its metabolites contribute to survival and proliferation of prostate cancer cells. We examined whether AKT plays a role in promoting cPLA2α action in prostate cancer cells. We found a concordant increase in pAKT and cPLA2α levels in prostate tissue of prostate epithelial-specific PTEN-knockout but not PTEN-wide type mice. Restoration of PTEN expression or inhibition of PI3K action decreased cPLA2α expression in PTEN-mutated or deleted prostate cancer cells. An increase in AKT by Myr-AKT elevated cPLA2α protein levels, which could be diminished by inhibition of AKT phosphorylation without noticeable change in total AKT levels. pAKT levels had no influence on cPLA2α at mRNA levels but reduced cPLA2α protein degradation. Anti-AKT antibody co-immunoprecipitated cPLA2α and vice versa. Hence, AKT plays a role in enhancing cPLA2α protein stability in PTEN-null prostate cancer cells, revealing a link between oncogenic pathway and lipid metabolism.

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Enhanced antitumor activity of cerulenin combined with oxaliplatin in human colon cancer cells

Cited by 67 publications

References 28 publications

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

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

Linc00152 Functions as a Competing Endogenous RNA to Confer Oxaliplatin Resistance and Holds Prognostic Values in Colon Cancer

Loss of PTEN stabilizes the lipid modifying enzyme cytosolic phospholipase A2α via AKT in prostate cancer cells

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