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Downregulation of ceramide synthase 1 promotes oral cancer through endoplasmic reticulum stress.

ABSTRACT: C18 ceramide plays an important role in the occurrence and development of oral squamous cell carcinoma. However, the function of ceramide synthase 1, a key enzyme in C18 ceramide synthesis, in oral squamous cell carcinoma is still unclear. The aim of our study was to investigate the relationship between ceramide synthase 1 and oral cancer. In this study, we found that the expression of ceramide synthase 1 was downregulated in oral cancer tissues and cell lines. In a mouse oral squamous cell carcinoma model induced by 4-nitroquinolin-1-oxide, ceramide synthase 1 knockout was associated with the severity of oral malignant transformation. Immunohistochemical studies showed significant upregulation of PCNA, MMP2, MMP9, and BCL2 expression and downregulation of BAX expression in the pathological hyperplastic area. In addition, ceramide synthase 1 knockdown promoted cell proliferation, migration, and invasion in vitro. Overexpression of CERS1 obtained the opposite effect. Ceramide synthase 1 knockdown caused endoplasmic reticulum stress and induced the VEGFA upregulation. Activating transcription factor 4 is responsible for ceramide synthase 1 knockdown caused VEGFA transcriptional upregulation. In addition, mild endoplasmic reticulum stress caused by ceramide synthase 1 knockdown could induce cisplatin resistance. Taken together, our study suggests that ceramide synthase 1 is downregulated in oral cancer and promotes the aggressiveness of oral squamous cell carcinoma and chemotherapeutic drug resistance.

SUBMITTER: Chen W

PROVIDER: S-EPMC7985500 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Pancreatic ductal adenocarcinoma (PDAC) shows a high level of basal autophagy. Here we investigated the role of optineurin (OPTN) in PDAC cell lines, which is a prominent member of the autophagy system. To that purpose, mining of publically available databases showed that OPTN is highly expressed in PDAC and that high levels of expression are related to reduced survival. Therefore, the role of OPTN on proliferation, migration, and colony formation was investigated by transient knockdown in Miapaca, BXPC3, and Suit2-007 human PDAC cells. Furthermore, gene expression modulation in response to OPTN knockdown was assessed by microarray. The influence on cell cycle distribution and cell death signaling cascades was followed by FACS, assays for apoptosis, RT-PCR, and western blot. Finally, autophagy and ROS induction were screened by acridine orange and DCFH-DA fluorescent staining respectively. OPTN knockdown caused significant inhibition of colony formation, increased migration and no significant effect on proliferation in Miapaca, BXPC3 and Suit2-007 cells. The microarray showed modulation of 293 genes in Miapaca versus 302 in Suit2-007 cells, of which 52 genes overlapped. Activated common pathways included the ER stress response and chaperone-mediated autophagy, which was confirmed at mRNA and protein levels. Apoptosis was activated as shown by increased levels of cleaved PARP, Annexin V binding and nuclear fragmentation. OPTN knockdown caused no increased vacuole formation as assessed by acridine orange. Also, there was only marginally increased ROS production. Combination of OPTN knockdown with the autophagy inducer erufosine or LY294002, an inhibitor of autophagy, showed additive effects, which led us to hypothesize that they address different pathways. In conclusion, OPTN knockdown was related to activation of ER stress response and chaperone-mediated autophagy, which tend to confine the damage caused by OPTN knockdown and thus question its value for PDAC therapy.

Project description:AimsChronic alcohol abuse causes steatohepatitis with insulin resistance, which impairs hepatocellular growth, survival and metabolism. However, growing evidence supports the concept that progressive alcohol-related liver injury may be mediated by concurrent mal-signaling through other networks that promote insulin resistance, e.g. pro-inflammatory, pro-ceramide and endoplasmic reticulum (ER) stress cascades.MethodsUsing the Long Evans rat model of chronic ethanol feeding, we characterized the histopathologic and ultrastructural features of steatohepatitis in relation to biochemical and molecular indices of tissue injury, inflammation, insulin resistance, dysregulated lipid metabolism and ER stress.ResultsChronic steatohepatitis with early chicken-wire fibrosis was associated with enlargement of mitochondria and disruption of ER structure by electron microscopy, elevated indices of lipid storage, lipid peroxidation and DNA damage, increased activation of pro-inflammatory cytokines, impaired signaling through the insulin receptor (InR), InR substrate-1, Akt, ribosomal protein S6 kinase and proline-rich Akt substrate 40 kDa, glycogen synthase kinase 3β activation and constitutive up-regulation of ceramide and ER stress-related genes. Liquid chromatography coupled with tandem mass spectrometry demonstrated altered ceramide profiles with higher levels of C14 and C18, and reduced C16 species in ethanol-exposed livers.ConclusionThe histopathologic and ultrastructural abnormalities in chronic alcohol-related steatohepatitis are associated with persistent hepatic insulin resistance and pro-inflammatory cytokine activation, dysregulated lipid metabolism with altered ceramide profiles and both ER and oxidative stress. Corresponding increases in lipid peroxidation, DNA damage and protein carbonylation may have contributed to the chronicity and progression of disease. The findings herein suggest that multi-pronged therapeutic strategies may be needed for effective treatment of chronic alcoholic liver disease in humans.

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Downregulation of ceramide synthase 1 promotes oral cancer through endoplasmic reticulum stress.

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