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t细胞白血病病毒（HTLV-1）后发生。SIRT1是一种烟酰胺腺嘌呤二核苷酸（+）依赖性组蛋白/蛋白去乙酰化酶，在衰老、代谢、神经发生和细胞凋亡等多种生理过程中起着至关重要的作用，因为SIRT1能够使许多底物（如组蛋白和NF-κB）去乙酰化，而组蛋白和NF-κB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被调节的。ATL患者SIRT1表达明显高于健康对照组，尤其是急性型。Sirtinol是一种SIRT1抑制剂，可诱导ATL患者和白血病细胞系，特别是htlv -1相关细胞系的细胞显著生长抑制或凋亡。sirtinol诱导的细胞凋亡是通过激活caspase家族和降解细胞核中的SIRT1介导的。此外，SIRT1特异性小干扰RNA敲低SIRT1通过激活MT-2细胞、htlv -1相关细胞系的caspase-3和PARP导致细胞凋亡。这些结果表明SIRT1是ATL细胞中一个重要的抗凋亡分子，SIRT1抑制剂可能是治疗白血病的有效药物，特别是对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.