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

Abstract

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.