Nishimoto T, Kimura R, Matsumoto A, Sugimoto H
Department of Immunology, Kawasaki Medical School, Okayama, 701-0192, Japan.
Arts and Sciences, Faculty of Engineering, Tokyo University of Science, Yamaguchi, 756-0884, Japan.
Cell Mol Biol (Noisy-le-grand). 2016 Oct 31;62(12):74-78. doi: 10.14715/cmb/2016.62.12.13.
Streptozotocin (STZ), a naturally occurring chemical, is toxic to the various kinds of cells such as insulin-producing beta cells. However, the beneficial effect of STZ on neuronal cells such as neurite outgrowth-inducing activity has been unknown. In this study, we examined the effect of STZ on neurite outgrowth in mouse neuronal Neuro2a cells. STZ (0.01 mM5 mM) exerted remarkable neurite outgrowth-inducing activity in Neuro2a cells in a concentration dependent manner. STZ also had the same neurite outgrowth-inducing activity as that of retinoic acid (RA), which is well known neurite outgrowth inducer. As with the result of RA treatment, STZ administration increased MAP2-positive cells. The MAP2-positive cells reflect neurite outgrowth-induced cells. STZ (0.01 mM5 mM) did not induce cell death, but significantly decreased cell proliferation. The serine/threonine kinase Akt, a downstream target of phosphatidylinositol-3 kinase (PI3K), was transiently phosphorylated at Ser473 and at Thr303 by STZ (5 mM) administration. Glycogen synthase kinase 3β (GSK3β), which has been reported to be inactivated by Akt, was also transiently phosphorylated at Ser9 by STZ (5 mM) administration. In addition, a blocker of PI3K, LY294002 (10 μM), significantly attenuated STZ-induced neurite outgrowth. These results suggest that STZ induces neurite outgrowth via activation of PI3K-Akt signaling pathway and GSK3β inhibition.
链脲佐菌素（STZ）是一种天然存在的化学物质，对各种细胞如产生胰岛素的β细胞有毒性。然而，STZ对神经元细胞的有益作用，如神经突生长诱导活性，一直不为人知。在本研究中，我们检测了STZ对小鼠神经元Neuro2a细胞神经突生长的影响。STZ（0.01 mM至5 mM）以浓度依赖的方式在Neuro2a细胞中发挥显著的神经突生长诱导活性。STZ还具有与视黄酸（RA）相同的神经突生长诱导活性，视黄酸是一种众所周知的神经突生长诱导剂。与RA处理的结果一样，给予STZ可增加微管相关蛋白2（MAP2）阳性细胞。MAP2阳性细胞反映了神经突生长诱导的细胞。STZ（0.01 mM至5 mM）未诱导细胞死亡，但显著降低了细胞增殖。丝氨酸/苏氨酸激酶Akt是磷脂酰肌醇-3激酶（PI3K）的下游靶点，给予STZ（5 mM）后，其在Ser473和Thr303处短暂磷酸化。糖原合酶激酶3β（GSK3β）据报道可被Akt灭活，给予STZ（5 mM）后，其在Ser9处也短暂磷酸化。此外，PI3K的抑制剂LY294002（10 μM）显著减弱了STZ诱导的神经突生长。这些结果表明，STZ通过激活PI3K-Akt信号通路和抑制GSK3β诱导神经突生长。
