Research Paper Volume 12, Issue 12 pp 11364—11385
Sirt1 gene confers Adriamycin resistance in DLBCL via activating the PCG-1α mitochondrial metabolic pathway
- 1 Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China
- 2 Department of Pharmacy, Affiliated Baiyun Hospital of Guizhou Medical University, Guiyang 550004, China
- 3 Key Laboratory of Hematological Disease Diagnostic and Treat Centre of Guizhou Province, Guiyang 550004, China
- 4 Department of Hematology, Guizhou Provincial Laboratory of Hematopoietic Stem Cell Transplantation Center, Guiyang 550004, China
- 5 Department of Pharmacy, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China
- 6 Department of Clinical Research Center, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China
- 7 Department of Psychiatry, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China
Received: July 30, 2019 Accepted: April 13, 2020 Published: June 22, 2020https://doi.org/10.18632/aging.103174
How to Cite
Copyright © 2020 Zhou et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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.
ABC-DLBCL: activated B-cell-like DLBCL; COO: cell-of-origin; DLBCL: Diffuse large B-cell lymphoma; EGFP: enhanced green fluorescent protein; FCM: flow cytometry; FFPE: formalin-fixed paraffin embedded; GAPHD: glyceraldehyde-3-phosphate dehydrogenases; GCB-DLBCL: germinal-center B-cell–like DLBCL; Go analysis: gene ontology enrichment analysis; GSEA: gene set enrichment analysis; HCC: hepatocellular carcinoma; IHC: immunohistochemistry; NHL: non-hodgkin lymphoma; OS: overall survival; OxPhos-DLBCLs: oxidative phosphorylation in DLBCL patients; PFS: progression-free Survival; PPAR: peroxisome proliferator-activated receptor.