Fatty acid 2-hydroxylation inhibits tumor growth and increases sensitivity to cisplatin in gastric cancer

Yao, Yizhou; Yang, Xiaoqin; Sun, Liang; Sun, Shishuo; Huang, Xiaoheng; Zhou, Diyuan; Li, Tingting; Zhang, Wei; Abumrad, Nada A.; Zhu, Xinguo; He, Songbing; Su, Xiong

doi:10.1016/j.ebiom.2019.01.066

Cited by 57 publications

(86 citation statements)

References 50 publications

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“…The survival rate of AGS cells varied depending on the expression levels of TC2N; TC2N knockdown significantly decreased the cell survival rate, reflecting a higher sensitivity of AGS cells to DPP, paclitaxel and 5-FU when TC2N expression was inhibited. Acquired drug resistance is one of the predominant reasons for the low cure rate and high recurrence rate in patients with gastric cancer, especially at an advanced stage ( 23 ). Thus, improving the sensitivity of cancer cells to chemotherapeutics may be an important strategy for cancer treatment.…”

Section: Discussionmentioning

confidence: 99%

Tac2‑N serves an oncogenic role and promotes drug resistance in human gastric cancer cells

et al. 2020

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Gastric cancer is one of the most common types of malignancy worldwide. Tac2-N (TC2N) has been reported to serve as either an oncogene or tumor suppressor in numerous different types of cancer; however, the role of TC2N in gastric cancer remains poorly understood. The present study aimed to investigate the role of TC2N in gastric cancer and reveal its regulatory mechanism. A Cell Counting Kit-8 assay was used to analyze the cell proliferation rate, while wound healing and Transwell Matrigel assays were performed to determine the cell migratory and invasive abilities, respectively. Cell cycle distribution was determined by flow cytometric analysis, and the expression levels of TC2N, P-glycoprotein (P-gp), cyclin D1, CDK4, cyclin E1, MMP2, MMP9 and N-Myc downstream regulated gene 1 were analyzed using reverse transcription-quantitative PCR or western blotting. Bioinformatics analysis revealed a high expression of TC2N in patients with gastric cancer. The experimental results revealed that TC2N expression levels were significantly unregulated in gastric cancer cell lines. The knockdown of TC2N in AGS cells significantly inhibited the cell proliferation rate and induced cell cycle arrest at the G0/G1 phase, while downregulating cyclin E1, cyclin D1 and CDK4 expression levels. The knockdown of TC2N also inhibited cell migration and invasion. Furthermore, the knockdown of TC2N improved the sensitivity of AGS cells to cisplatin, paclitaxel and 5-fluorouracil, and downregulated the protein expression levels of P-gp. By contrast, TC2N overexpression exerted the opposite effects in AGS cells. In conclusion, the findings of the present study indicated that the genetic knockdown of TC2N may inhibit cell proliferation, migration and invasion, while inducing cell cycle arrest in the G1/S phase and reversing the drug resistance of AGS cells, which may be partly through inhibiting P-gp expression levels. Thus, TC2N may serve as a novel diagnostic marker and therapeutic target for patients with gastric cancer.

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Section: Discussionmentioning

confidence: 99%

Tac2‑N serves an oncogenic role and promotes drug resistance in human gastric cancer cells

et al. 2020

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“…Our results strongly argue that a combination of FA2H and UGT8 expression drives the synthesis of 2-hydroxyHexCer, the exact mechanism accounting for the accumulation of these metabolites specifically in adenocarcinomas, which should be confirmed by ulterior investigations of sulfatides and gangliosides, which were also linked with cancer metastasis (35,36) and multi-drug resistance (37). Aligning with the theory that complex metabolic alterations, rather than single molecule levels, should be taken into account for delineating mechanisms of disease, low FA2H was associated with tumor growth and patient survival in gastric tumors (38), but UGT8 is not overexpressed in gastric tumors in Fig. 2.…”

Section: Discussionmentioning

confidence: 88%

High FA2H and UGT8 transcript levels predict hydroxylated hexosylceramide accumulation in lung adenocarcinoma

Lemay

Courtemanche

Couttas

et al. 2019

Journal of Lipid Research

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Supplementary key words 2-hydroxyhexosylceramide • sphingolipid • squamous • neuroendocrine • cancer • fatty acids • gene expression • mass spectrometry • fatty acid 2-hydroxylase • uridine 5′-diphosphateglycosyltransferase 8 Lung cancer is the leading cause of cancer-related deaths worldwide, with an estimated 1.8 million deaths per year (1). The overall prognosis of lung cancer patients is poor, with an 18% survival rate after 5 years (1). Given the clinical advantage of cancer type-specific therapies, it is required to enhance our understanding of differential mechanisms underlying lung cancers. Sphingolipid alterations are increasingly associated with oncogenesis (2). Sphingolipids encompass a wide array of bioactive molecules centrally involved in the determination Abstract Lung cancer causes more deaths than any other cancer. Sphingolipids encompass metabolically interconnected species whose balance has pivotal effects on proliferation, migration, and apoptosis. In this study, we paralleled quantification of sphingolipid species with quantitative (q) PCR analyses of metabolic enzymes in order to identify dysregulated routes of sphingolipid metabolism in different subtypes of lung cancers. Lung samples were submitted to histopathological reexamination in order to confirm cancer type/subtype, which included adenocarcinoma histological subtypes and squamous cell and neuroendocrine carcinomas. Compared with benign lesions and tumor-free parenchyma, all cancers featured decreased sphingosine-1-phosphate and SMs. qPCR analyses evidenced differential mechanisms leading to these alterations between cancer types, with neuroendocrine carcinomas upregulating SGPL1, but CERT1 being downregulated in adenocarcinomas and squamous cell carcinomas. 2-Hydroxyhexosylceramides (2-hydroxyHexCers) were specifically increased in adenocarcinomas. While UDPglycosyltransferase 8 (UGT8) transcript levels were increased in all cancer subtypes, fatty acid 2-hydroxylase (FA2H) levels were higher in adenocarcinomas than in squamous and neuroendocrine carcinomas. As a whole, we report differing mechanisms through which all forms of lung cancer achieve low SM and lysosphingolipids. Our results also demonstrate that FA2H upregulation is required for the accumulation of This study was funded using peer-reviewed grants from the Cancer Research Society (Grant 22339) (70%) and from the Faculty of Medicine of Université Laval using funds from a donation by Merck Sharpe and Dohme (30%). The latter company did not have any involvement in any step of this project.

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“…FA2H downregulation has been observed in triple negative breast cancer tissues and cell lines (27). FA2H expression levels were lower in gastric tumor tissues compared with healthy control tissues (26). Moreover, another study revealed that FA2H levels were higher in adenocarcinoma compared with squamous and neuroendocrine carcinoma (28).…”

Section: Microrna-1297 Downregulation Inhibits Breast Cancer Cell Epimentioning

confidence: 98%

“…As a hydroxy fatty acid enzyme, fatty acid 2-hydroxylase (FA2H) promotes 2-hydroxylation of fatty acid N-acyl chain (23). It has been reported that 2-hydroxyceramide and FA2H, which are expressed in several tissues (24,25), participate in multiple cell signaling pathways, such as the AMPK and mTOR/p70 ribosomal protein S6 kinase 1 (S6K1)/glioma-associated oncogene homolog 1 pathways (26). FA2H also serves a crucial role in the occurrence and development of tumors (26).…”

Section: Microrna-1297 Downregulation Inhibits Breast Cancer Cell Epimentioning

confidence: 99%

“…It has been reported that 2-hydroxyceramide and FA2H, which are expressed in several tissues (24,25), participate in multiple cell signaling pathways, such as the AMPK and mTOR/p70 ribosomal protein S6 kinase 1 (S6K1)/glioma-associated oncogene homolog 1 pathways (26). FA2H also serves a crucial role in the occurrence and development of tumors (26). FA2H downregulation has been observed in triple negative breast cancer tissues and cell lines (27).…”

Section: Microrna-1297 Downregulation Inhibits Breast Cancer Cell Epimentioning

confidence: 99%

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MicroRNA‑1297 downregulation inhibits breast cancer cell epithelial‑mesenchymal transition and proliferation in a FA2H‑dependent manner

Lian

Liu

et al. 2020

Oncol Lett

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Breast cancer (BC) is one of the most common malignant tumors among women worldwide. MicroRNAs (miRs) may be involved in several types of human cancer, including gastric, liver, lung and breast cancer. The aim of the present study was to investigate the effect of miR-1297 on MDA-MB-231 cell epithelial-mesenchymal transition (EMT) and proliferation, and the underlying molecular mechanisms. MDA-MB-231 cells were transfected with miR-1297 inhibitor or inhibitor control for 48 h. Subsequently, MTT and flow cytometry assays indicated that miR-1297 inhibitor significantly decreased cell proliferation and induced apoptosis compared with the inhibitor control group. In addition, reverse transcription-quantitative PCR and western blotting suggested that miR-1297 inhibitor suppressed EMT in MDA-MB-231 cells compared with the inhibitor control group. TargetScan bioinformatics analysis and a dual-luciferase reporter gene assay were performed, which predicted that miR-1297 directly targeted fatty acid 2-hydroxylase (FA2H). Furthermore, MDA-MB-231 cells were transfected with control-plasmid or FA2H-plasmid for 48 h. The results demonstrated that FA2H overexpression decreased MDA-MB-231 cell proliferation and increased apoptosis compared with the control-plasmid group. Additionally, FA2H-plasmid increased E-cadherin expression levels, and reduced N-cadherin and matrix metalloproteinase 9 expression levels at both the protein and mRNA level compared with control-plasmid. Finally, MDA-MB-231 cells were transfected with control-small interfering (si) RNA, FA2H-siRNA, inhibitor control, miR-1297 inhibitor, miR-1297 inhibitor + control siRNA or miR-1297 inhibitor + FA2H-siRNA, and the results suggested that the biological effects of miR-1297 inhibitor were reversed by co-transfection with FA2H siRNA. In conclusion, the present study indicated that miR-1297/FA2H might serve as a novel potential biomarker and therapeutic target for BC.

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Fatty acid 2-hydroxylation inhibits tumor growth and increases sensitivity to cisplatin in gastric cancer

Cited by 57 publications

References 50 publications

Tac2‑N serves an oncogenic role and promotes drug resistance in human gastric cancer cells

Tac2‑N serves an oncogenic role and promotes drug resistance in human gastric cancer cells

High FA2H and UGT8 transcript levels predict hydroxylated hexosylceramide accumulation in lung adenocarcinoma

MicroRNA‑1297 downregulation inhibits breast cancer cell epithelial‑mesenchymal transition and proliferation in a FA2H‑dependent manner

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