Department of Molecular Hematopoiesis, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany.
Haematologica. 2012 Apr;97(4):551-9. doi: 10.3324/haematol.2011.055236. Epub 2011 Dec 29.
Inhibitors of nicotinamide phosphoribosyltransferase have recently been validated as therapeutic targets in leukemia, but the mechanism of leukemogenic transformation downstream of this enzyme is unclear.
Here, we evaluated whether nicotinamide phosphoribosyltransferase's effects on aberrant proliferation and survival of myeloid leukemic cells are dependent on sirtuin and delineated the downstream signaling pathways operating during this process.
We identified significant upregulation of sirtuin 2 and nicotinamide phosphoribosyltransferase levels in primary acute myeloid leukemia blasts compared to in hematopoietic progenitor cells from healthy individuals. Importantly, specific inhibition of nicotinamide phosphoribosyltransferase or sirtuin 2 significantly reduced proliferation and induced apoptosis in human acute myeloid leukemia cell lines and primary blasts. Intriguingly, we found that protein kinase B/AKT could be deacetylated by nicotinamide phosphoribosyltransferase and sirtuin 2. The anti-leukemic effects of the inhibition of nicotinamide phosphoribosyltransferase or sirtuin 2 were accompanied by acetylation of protein kinase B/AKT with subsequent inhibition by dephosphorylation. This leads to activation of glycogen synthase kinase-3 β via diminished phosphorylation and, ultimately, inactivation of β-catenin by phosphorylation.
Our results provide strong evidence that nicotinamide phosphoribosyltransferase and sirtuin 2 participate in the aberrant proliferation and survival of leukemic cells, and suggest that the protein kinase B/AKT/ glycogen synthase kinase-3 β/β-catenin pathway is a target for inhibition of nicotinamide phosphoribosyltransferase or sirtuin 2 and, thereby, leukemia cell proliferation.
烟酰胺磷酸核糖转移酶抑制剂最近已被验证为白血病的治疗靶点，但该酶下游导致白血病转化的机制尚不清楚。
本研究评估了烟酰胺磷酸核糖转移酶对髓系白血病细胞异常增殖和存活的影响是否依赖于沉默调节蛋白，并描绘了在此过程中起作用的下游信号通路。
与健康个体的造血祖细胞相比，我们在原发性急性髓系白血病blasts 中发现沉默调节蛋白 2 和烟酰胺磷酸核糖转移酶水平显著上调。重要的是，烟酰胺磷酸核糖转移酶或沉默调节蛋白 2 的特异性抑制可显著降低人急性髓系白血病细胞系和原发性blasts 的增殖并诱导其凋亡。有趣的是，我们发现蛋白激酶 B/AKT 可被烟酰胺磷酸核糖转移酶和沉默调节蛋白 2 去乙酰化。烟酰胺磷酸核糖转移酶或沉默调节蛋白 2 抑制的抗白血病作用伴随着蛋白激酶 B/AKT 的乙酰化，随后通过去磷酸化抑制。这导致通过磷酸化减少糖原合酶激酶-3β的激活，并最终通过磷酸化使β-连环蛋白失活。
我们的研究结果提供了有力的证据表明烟酰胺磷酸核糖转移酶和沉默调节蛋白 2 参与白血病细胞的异常增殖和存活，并表明蛋白激酶 B/AKT/糖原合酶激酶-3β/β-连环蛋白通路是抑制烟酰胺磷酸核糖转移酶或沉默调节蛋白 2 的靶点，从而抑制白血病细胞增殖。
