SIRT1, a longevity gene encoded protein, regulates apoptosis of adult T-cell leukemia cells and its inhibition by sirtinol induces apoptosis

成人T细胞白血病淋巴瘤（ATL）是一种侵袭性外周T细胞肿瘤，在长期感染人类T细胞白血病病毒（HTLV-1）后发展。SIRT 1是一种依赖于烟酰胺腺嘌呤二核苷酸（+）的组蛋白/蛋白脱乙酰酶，由于其能够使许多底物（如组蛋白和NF-κ B）脱乙酰化，其在诸如衰老、代谢、神经发生和细胞凋亡的各种生理过程中起关键作用，NF-κ B被认为是ATL的加重因子。在这里，我们评估了SIRT1是如何在原代ATL细胞和白血病细胞系中调节的。SIRT1在ATL患者中的表达明显高于健康对照组，尤其是急性型。SIRT1抑制剂Sirtinol在ATL患者和白血病细胞系，特别是HTLV-1相关细胞系中诱导显著的生长抑制或凋亡。Sirtinol诱导的细胞凋亡是通过caspase家族的激活和细胞核中SIRT1的降解介导的。此外，SIRT1特异性小干扰RNA敲低SIRT1可通过激活MT-2细胞（HTLV-1相关细胞系）中的caspase-3和PARP引起细胞凋亡。这些结果表明，SIRT1是一个重要的抗凋亡分子在ATL细胞和SIRT1抑制剂可能是有用的治疗剂白血病，特别是在ATL患者。

Adult T-cell leukemia-lymphoma(ATL) is an aggressive peripheral T-cell neoplasm that develops after long-term infection with human T-cell leukemia virus(HTLV-1). SIRT1, a nicotinamide adenine dinucleotide(+)-dependent histone/protein deacetylase, plays a crucial role in various physiological processes, such as aging, metabolism, neurogenesis and apoptosis, owing to its ability to deacetylate numerous substrates, such as histone and NF-κB, which is implicated as an exacerbation factor in ATL. Here, we assessed how SIRT1 is regulated in primary ATL cells and leukemic cell lines. SIRT1 expression in ATL patients was significantly higher than that in healthy controls, especially in the acute type. Sirtinol, a SIRT1 inhibitor, induced significant growth inhibition or apoptosis in cells from ATL patients and leukemic cell lines, especially HTLV-1-related cell lines. Sirtinol-induced apoptosis was mediated by activation of the caspase family and degradation of SIRT1 in the nucleus. Furthermore, SIRT1 knockdown by SIRT1-specific small interfering RNA caused apoptosis via activation of caspase-3 and PARP in MT-2 cells, HTLV-1-related cell line. These results suggest that SIRT1 is a crucial antiapoptotic molecule in ATL cells and that SIRT1 inhibitors may be useful therapeutic agents for leukemia, especially in patients with ATL.