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S100A8 promotes chemoresistance via augmenting autophagy in B?cell lymphoma cells.

ABSTRACT: B?cell lymphomas (BCLs) are malignant lymphoid tumours originating from the malignant proliferation and transformation of mature lymphocytes at various stages of differentiation and clonal expansion of the lymphatic and circulatory systems. Efforts to control or even eradicate BCLs are frequently hampered by the development of drug resistance. Autophagy is an evolutionarily conserved biological process of the energy metabolism. By degrading intracellular organelles and proteins, autophagy provides cells with biochemical reaction substrates for the maintenance of homeostasis under nutrient deprivation or other stressful conditions. Accumulating evidence indicates that autophagy plays an important role in chemotherapy resistance. S100A8 is an important member of the calcium?binding protein family that plays an important role in regulating tumour resistance to chemotherapy, while the specific molecular regulatory mechanisms remain unclear. In the present study, by employing three BCL cell lines (Daudi, SUDHL?4 and JeKo?1), it was demonstrated that BCL cells with a strong drug resistance also exhibited active autophagy. In addition, S100A8 was found to be crucial for regulating drug resistance and promoting autophagy in BCL cells. Interference of S100A8 significantly downregulated Bcl?2/adenovirus E1B 19?kDa protein?interacting protein 3 located in the mitochondria and endoplasmic reticulum to further inhibit autophagy. In addition, S100A8 interference markedly inhibited the formation of the BECN1?PI3KC3 complex and promoted B?cell lymphoma 2 expression, which collectively inhibited autophagy.

SUBMITTER: Zhang L

PROVIDER: S-EPMC7709824 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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S100A8 promotes chemoresistance via augmenting autophagy in B‑cell lymphoma cells.

Zhang Li L Zhou Shixia S Zhou Tiejun T Yuan Kaifeng K Li Xiaoming X Tang Junling J

Oncology reports 20201109 1

B‑cell lymphomas (BCLs) are malignant lymphoid tumours originating from the malignant proliferation and transformation of mature lymphocytes at various stages of differentiation and clonal expansion of the lymphatic and circulatory systems. Efforts to control or even eradicate BCLs are frequently hampered by the development of drug resistance. Autophagy is an evolutionarily conserved biological process of the energy metabolism. By degrading intracellular organelles and proteins, autophagy provid ...[more]

PMID: 33169801

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Project description:BackgroundChemotherapy is one of the primary treatments for ovarian cancer patients. Autophagy has been linked to chemotherapy resistance in tumor cells. Recent studies have suggested that fibroblast growth factor 19 (FGF19) may be involved in the onset and progression of malignancies. However, the relationship between FGF19 and autophagy in ovarian cancer is still unknown.MethodsNext-generation sequencing (NGS) was conducted to analyze gene mutation profiles of 62 cases of high grade serous ovarian cancer (HGSOC). Fluorescence in situ hybridization (FISH) was performed to validate the amplification of FGF19 in HGSOC tissues. Quantitative PCR (qPCR) and immunohistochemistry (IHC) were used to analyze the difference of FGF19 in mRNA and protein expression. Meanwhile, bioinformatics techniques were used to analyze the expression profiles of FGF19 and the correlation with prognosis. Besides, immunofluorescence, transmission electron microscopy and Cell Counting Kit 8 (CCK-8) were used to investigate the potential mechanisms.ResultsIn this study, we found that FGF19 promotes cisplatin resistance in ovarian cancer cells by inducing autophagy. NGS analysis of 62 HGSOC cases identified a significantly amplified gene, FGF19. In addition, the expression level of FGF19 in ovarian cancer samples was higher than that in normal samples. FISH results showed a positive correlation between amplification and expression of FGF19. Knockdown of FGF19 inhibited the cell autophagy through decrease in the expression of LC3 and Beclin 1, and increase in the expression of SQSTM1/p62. Furthermore, we observed that p38 MAPK phosphorylation was down-regulated after FGF19 knockdown. IFN-γ, a potential p38 MAPK activator, counteracted the inhibition of cell autophagy and the anti-proliferation effect of cisplatin induced by FGF19 knockdown in ovarian cancer cells.ConclusionFGF19 increases autophagy and chemoresistance in ovarian cancer by activating the p38 MAPK pathway. These results could point to FGF19 being a potential therapeutic target for ovarian cancer.

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S100A8 promotes chemoresistance via augmenting autophagy in B?cell lymphoma cells.

Publications

S100A8 promotes chemoresistance via augmenting autophagy in B‑cell lymphoma cells.

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