SUTAF, a novel β-methoxyacrylate derivative, promotes neurite outgrowth with extracellular signal-regulated kinase and c-jun N-terminal kinase activation

beta-Methoxyacrylate antibiotics are well known to inhibit the fungal and yeast mitochondrial respiratory chain. In addition, beta-methoxyacrylates are reported to suppress the proliferation of mammalian cancer cells. Differentiation and cell-cycle arrest are closely related. The cell cycle of proliferating cells is suppressed before differentiation. In this study, we synthesized a beta-methoxyacrylate analog and treated neuronal differential model cells with it. We then estimated beta-methoxyacrylate's neurotrophic effect by inhibiting cell proliferation so as to orient neuronal differentiation. SUTAF-027-a novel beta-methoxyacrylate derivative, arrested the cell cycle and thereby suppressed the proliferation of PC12 rat pheochromocytoma cells and mouse neuroblastoma Neuro2a cells at very low treatment doses, as low as 1 nM. However, a single SUTAF-027 treatment did not affect neuritogenesis. Surprisingly, however, co-treatment of SUTAF-027 and nerve growth factor (NGF) significantly augmented the NGF-induced neurite outgrowth of PC12. On the other hand, a single treatment of 1 nM SUTAF-027 induced neurite outgrowth in Neuro2a cells. Further signal transduction mechanism studies revealed that SUTAF-027 induced the phosphorylation of extracellular signal-regulated kinase (ERK) and slight phosphorylation of c-jun N-terminal kinase (JNK). Moreover, inhibition of ERK and JNK blocked SUTAF-027-augmented neurite outgrowth. These results suggested that the novel beta-methoxyacrylate analog SUTAF-027 augmented neurite outgrowth by arresting the cell cycle and activating the ERK and INK pathways. (c) 2012 Elsevier B.V. All rights reserved.