Synergistic effect of 15-lipoxygenase 2 and radiation in killing head-and-neck cancer

Yang, Qiuhui; Feng, Yanjun; Schultz, Chris; Li, X A; Wang, Hui; Wang, D

doi:10.1038/cgt.2008.9

Cited by 12 publications

(8 citation statements)

References 29 publications

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“…Although the regulation of lipoxygenases, such as 15-LOX-2, 12-LO and 5-LO, has been shown in several reports to contribute to radiosensitivity [22,23,24], this study constitutes the first analysis of the relationship between 15-LOX-1 expression and radiation response in CRC cell lines. We measured the radiosensitivity of CRC cell lines by using clonogenic cell survival assays (Figure 1A).…”

Section: Resultsmentioning

confidence: 96%

Deficiency of 15-LOX-1 Induces Radioresistance through Downregulation of MacroH2A2 in Colorectal Cancer

Kim

et al. 2019

Cancers

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Despite the importance of radiation therapy, there are few radiation-related markers available for use in clinical practice. A larger catalog of such biomarkers is required to help clinicians decide when radiotherapy should be replaced with a patient-specific treatment. Arachidonate 15-lipoxygenase (15-LOX-1) enzyme is involved in polyunsaturated fatty acid metabolism. When colorectal cancer (CRC) cells were exposed to radiation, 15-LOX-1 was upregulated. To verify whether 15-LOX-1 protects against or induces DNA damage, we irradiated sh15-LOX-1 stable cells. We found that low 15-LOX-1 is correlated with radioresistance in CRC cells. These data suggest that the presence of 15-LOX-1 can be used as a marker for radiation-induced DNA damage. Consistent with this observation, gene-set-enrichment analysis based on microarray experiments showed that UV_RESPONSE was decreased in sh15-LOX-1 cells compared to shCon cells. Moreover, we discovered that the expression of the histone H2A variant macroH2A2 was sevenfold lower in sh15-LOX-1 cells. Overall, our findings present mechanistic evidence that macroH2A2 is transcriptionally regulated by 15-LOX-1 and suppresses the DNA damage response in irradiated cells by delaying H2AX activation.

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Section: Resultsmentioning

confidence: 96%

Deficiency of 15-LOX-1 Induces Radioresistance through Downregulation of MacroH2A2 in Colorectal Cancer

Kim

et al. 2019

Cancers

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“…There is increasing evidence to suggest that 15-LOX-1 and -2 are tumour functional suppressors since their levels are reduced in various types of human cancer,8 11 16 17 and the re-expression of 15-LOX-1 or -2 to restore their enzyme activities has been shown to inhibit tumour growth 10 18–21. Better differentiated NSCLC showed higher 15-LOX-2 expression and there was a significant inverse correlation between 15-LOX-2 expression and tumour grade 22.…”

Section: Discussionmentioning

confidence: 99%

15-Lipoxygenases and its metabolites 15(S)-HETE and 13(S)-HODE in the development of non-small cell lung cancer

Yuan

Lily

et al. 2010

Thorax

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Background 15-S-Hydroxyeicosatetraenoic acid (15(S)-HETE) and 13-S-hydroxyoctadecadienoic acid (13(S)-HODE), both of which are metabolites of 15-lipoxygenases (15-LOXs), are endogenous ligands for peroxisome proliferator-activated receptor gamma (PPARg). The activation of PPARg inhibits cell growth and induces apoptosis in some cancers. The role of 15(S)-HETE) and 13(S)-HODE in the development of lung cancer is not clear. Methods 15-LOXs, 15(S)-HETE and 13(S)-HODE were monitored during the development of mouse lung tumours induced by the tobacco smoke carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and the levels of these markers were determined in 54 human non-small cell lung cancers. INTRODUCTIONLung cancer is the most common cause of death from cancer in the world, with an overall 5-year survival rate of only 14% following diagnosis. Approximately 90% of all lung cancers are directly attributable to smoking. Lung cancer is divided into two major classes based on its biology, treatment and prognosis: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). NSCLC accounts for 80e85% of all cases of lung cancer and it includes three major types: squamous cell carcinoma, adenocarcinoma and large cell carcinoma. Despite advances in early detection and standard treatment, NSCLC is often diagnosed at an advanced stage. The heavy burden of lung cancer and the failure of effective approaches to reduce mortality have resulted in an interest in identifying signature biomarkers for lung cancer and target molecules for antitumour treatment.Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptor family consisting of a group of approximately 50 transcription factors implicated in many different biological processes, and are considered as important targets in the development of new drugs. The binding of ligands to receptors results in change of expression of mRNAs encoded by PPAR target genes. Activation of PPARg by its endogenous and exogenous ligands can inhibit cell proliferation and growth, and induce differentiation and apoptosis.3e5 Several studies have shown that the activation of PPARg can inhibit the growth of lung cancer cells.3 5 6 PPARg protein appears to correlate with the maturational stage of cells with a welldifferentiated phenotype in NSCLC.7 Well-differentiated NSCLC tissues frequently express more PPARg. However, the activation of PPARg is thought to be defective, 3 6e8 despite the high expression of PPARg in lung cancers.15-S-Hydroxyeicosatetraenoic acid (15(S)-HETE) and 13-S-hydroxyoctadecadienoic acid (13(S)-HODE), the two main metabolites of , are endogenous ligands of PPARg. They can inhibit cell proliferation and induce apoptosis in several types of human cancer.8e11 Two different types of human 15-LOXs have been found: 15-LOX-1 mainly metabolises linoleic acid (LA) to 13(S)-HODE but also converts arachidonic acid (AA) to 15(S)-HETE; 15-LOX-2 preferentially converts AA to 15(S)-HETE and metabolises LA poorly. Lungs express both of these...

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“…To re‐establish the production of 15(S)‐HETE and 13(S)‐HODE in these 2 cells, the cells were transfected with 15‐LOX‐1 and 15‐LOX‐2 expression plasmids, respectively. The cells were then incubated with LA or AA for 1 hour before the levels of 13(S)‐HODE or 15(S)‐HETE were detected by ELISA . To determine whether the levels of 15(S)‐HETE and 13(S)‐HODE were maintained during the incubation period in these transfected cells, the levels of these 2 metabolites were also detected in the cells 48 hours after the incubation.…”

Section: Methodsmentioning

confidence: 99%

“…The cells were then incubated with LA or AA for 1 hour before the levels of 13(S)-HODE or 15(S)-HETE were detected by ELISA. 13,26,28,29 To determine whether the levels of 15(S)-HETE and 13(S)-HODE were maintained during the incubation period in these transfected cells, the levels of these 2 metabolites were also detected in the cells 48 hours after the incubation.…”

Section: Measurement Of 15(s)-hete and 13(s)-hodementioning

confidence: 99%

Antineoplastic effects of 15(S)‐hydroxyeicosatetraenoic acid and 13‐S‐hydroxyoctadecadienoic acid in non–small cell lung cancer

et al. 2015

Cancer

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BACKGROUND Previous studies have shown that the levels of 15‐lipoxygenase 1 (15‐LOX‐1) and 15‐LOX‐2 as well as their metabolites 13‐S‐hydroxyoctadecadienoic acid (13(S)‐HODE) and 15(S)‐hydroxyeicosatetraenoic acid (15(S)‐HETE) are significantly reduced in smokers with non–small cell lung carcinoma (NSCLC). Furthermore, animal model experiments have indicated that the reduction of these molecules occurs before the establishment of cigarette smoking carcinogen–induced lung tumors, and this suggests roles in lung tumorigenesis. However, the functions of these molecules remain unknown in NSCLC. METHODS NSCLC cells were treated with exogenous 13(S)‐HODE and 15(S)‐HETE, and then the ways in which they affected cell function were examined. 15‐LOX‐1 and 15‐LOX‐2 were also overexpressed in tumor cells to restore these 2 enzymes to generate endogenous 13(S)‐HODE and 15(S)‐HETE before cell function was assessed. RESULTS The application of exogenous 13(S)‐HODE and 15(S)‐HETE significantly enhanced the activity of peroxisome proliferator‐activated receptor γ (PPARγ), inhibited cell proliferation, induced apoptosis, and activated caspases 9 and 3. The overexpression of 15‐LOX‐1 and 15‐LOX‐2 obviously promoted the endogenous levels of 13(S)‐HODE and 15(S)‐HETE, which were demonstrated to be more effective in the inhibition of NSCLC. CONCLUSIONS This study has demonstrated that exogenous or endogenous 13(S)‐HODE and 15(S)‐HETE can functionally inhibit NSCLC, likely by activating PPARγ. The restoration of 15‐LOX activity to increase the production of endogenous 15(S)‐HETE and 13(S)‐HODE may offer a novel research direction for molecular targeting treatment of smoking‐related NSCLC. This strategy can potentially avoid side effects associated with the application of synthetic PPARγ ligands. Cancer 2015;121:3130‐45. © 2015 American Cancer Society.

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Synergistic effect of 15-lipoxygenase 2 and radiation in killing head-and-neck cancer

Cited by 12 publications

References 29 publications

Deficiency of 15-LOX-1 Induces Radioresistance through Downregulation of MacroH2A2 in Colorectal Cancer

Deficiency of 15-LOX-1 Induces Radioresistance through Downregulation of MacroH2A2 in Colorectal Cancer

15-Lipoxygenases and its metabolites 15(S)-HETE and 13(S)-HODE in the development of non-small cell lung cancer

Antineoplastic effects of 15(S)‐hydroxyeicosatetraenoic acid and 13‐S‐hydroxyoctadecadienoic acid in non–small cell lung cancer

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