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.
Highlights
Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in adulthood, with the mid-age of 50-60, and more prevalent in elderly patients [1,2,3,4]
We found that Sirt1 protein to be significantly upregulated in diffuse large B-cell lymphoma (DLBCL) tumor tissues, including Non-GCB DLBCL tumor tissues, while it was only marginally detected in normal lymph node tissues (Figure 1A, 1B)
IHC analyses revealed that Sirt1 is significant upregulated at protein level in all four DLBCL cell lines and in DLBCL patient tissues, compared with that of CD19+ purified peripheral blood from normal B cells or normal lymph node tissues (Figure 1D), suggesting that Sirt1 is upregulated in human DLBCL cells
Summary
Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in adulthood, with the mid-age of 50-60, and more prevalent in elderly patients [1,2,3,4]. Tang reported that Sirt regulates embryonic stem cell maintenance and embryonic development, and indicated that Sirt plays a crucial role in the physiological functions of metabolism [14]. Liu reported that Sirt is highly expressed in liver cancer stem cells and decreases during differentiation, and that high levels of Sirt predict a decreased probability of survival of patients with HCC [20]. Kan reported that Sirt overexpression in DLBCL patients is a clinically significant poor prognostic indicator of DLBCL in the Chinese Han population [21]. These studies demonstrate that Sirt plays a vital role in chemotherapy resistance. The role and the molecular mechanism of Sirt in the aggression and treatment failure of DLBCL remains ambiguous
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