Sirt1 gene confers Adriamycin resistance in DLBCL via activating the PCG-1α mitochondrial metabolic pathway

Autor: Qin Fang, Jishi Wang, Zhen Zhou, Danna Wei, Peifan Li, Ping Liu, Ping Wang, Jun Wang, Dan Ma, Zhong Qin
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Adult
Male
Aging
chemotherapy resistance
endocrine system diseases
Peroxisome proliferator-activated receptor
Kaplan-Meier Estimate
PCG-1α
Adriamycin
Mice
Young Adult
Sirtuin 1
In vivo
hemic and lymphatic diseases
Cell Line
Tumor
Animals
Humans
RNA-Seq
Cytotoxicity
Receptor
Aged
chemistry.chemical_classification
Aged
80 and over
Membrane Potential
Mitochondrial
Sirt1
Chemistry
Acetylation
Cell Biology
Middle Aged
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Xenograft Model Antitumor Assays
Mitochondria
Up-Regulation
Blot
Gene Expression Regulation
Neoplastic
enzymes and coenzymes (carbohydrates)
Mitochondrial biogenesis
Cell culture
Doxorubicin
Drug Resistance
Neoplasm
DLBCL
Cancer research
lipids (amino acids
peptides
and proteins)
Female
Lymphoma
Large B-Cell
Diffuse
Signal transduction
hormones
hormone substitutes
and hormone antagonists
Metabolic Networks and Pathways
Research Paper
Zdroj: Aging (Albany NY)
ISSN: 1945-4589
Popis: Sirt1 is closely related to cells aging, and Sirt1 also plays an important role in diffuse large B-cell lymphoma (DLBCL). However, its mechanism remains unclear. Therefore, we investigated the mechanism of Sirt1 mediated drug-resistance in DLBCL, while the recombinant lentivirus was used to regulate Sirt1 gene expression in DLBCL cell lines. Subsequently, the effect of Sirt1 on DLBCL resistance to Adriamycin was analyzed in vitro. The results show that Sirt1 overexpression confers Adriamycin resistance in DLBCL cell lines. However, inhibition of Sirt1 sensitized DLBCL cell lines to Adriamycin cytotoxicity. Additionally, tumor-bearing mice were used to verify that Sirt1 overexpression confers Adriamycin resistance in vivo after chemotherapy. In addition, we used second-generation sequencing technology and bioinformatics analysis to find that Sirt1 mediated drug-resistance is related to the Peroxisome proliferator-activated receptor (PPAR) signaling pathway, especially to PGC-1α. Interestingly, the mitochondrial energy inhibitor, tigecycline, combined with Adriamycin reversed the cellular resistance caused by Sirt1 overexpression in vivo. Moreover, western blotting and CO-IP assay reconfirmed that Sirt1-mediated drug-resistance is associated with the increased expression of PGC1-α, which induce mitochondrial biogenesis. In summary, this study confirms that Sirt1 is a potential target for DLBCL treatment.
Databáze: OpenAIRE
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