The estrogen receptor β-PI3K/Akt pathway mediates the cytoprotective effects of tocotrienol in a cellular Parkinson's disease model.
Tocotrienols (T3s) are members of the vitamin E family, have antioxidant properties, and are promising candidates for neuroprotection in the pathogenesis of neurodegenerative disorders such as Parkinson's disease (PD). However, whether their antioxidant capacities are required for their cytoprotective activity remains unclear. In this regard, the antioxidant-independent cytoprotective activity of T3s has received considerable attention. Here, we investigated the signaling pathways that are induced during T3-dependent cytoprotection of human neuroblastoma SH-SY5Y cells, as these cells are used to model certain elements of PD. T3s were cytoprotective against 1-methyl-4-phenylpyridinium ion (MPP(+)) and other PD-related toxicities. γT3 and δT3 treatments led to marked activation of the PI3K/Akt signaling pathway. Furthermore, we identified estrogen receptor (ER) β as an upstream mediator of PI3K/Akt signaling following γT3/δT3 stimulation. Highly purified γT3/δT3 bound to ERβ directly in vitro, and knockdown of ERβ in SH-SY5Y cells abrogated both γT3/δT3-dependent cytoprotection and Akt phosphorylation. Since membrane-bound ERβ was important for the signal-related cytoprotective effects of γT3/δT3, we investigated receptor-mediated caveola formation as a candidate for the early events of signal transduction. Knockdown of caveolin-1 and/or caveolin-2 prevented the cytoprotective effects of γT3/δT3, but did not affect Akt phosphorylation. This finding suggests that T3s and, in particular, γT3/δT3, exhibit not only antioxidant effects but also a receptor signal-mediated protective action following ERβ/PI3K/Akt signaling. Furthermore, receptor-mediated caveola formation is an important event during the early steps following T3 treatment.
Division of Medical Biochemistry, Department of Pathophysiological and Therapeutic Sciences, Tottori University Faculty of Medicine, Yonago, Japan. Electronic address: kazuhiro@med.tottori-u.ac.jp.
Kazuhiro
K
Nakaso
Division of Medical Biochemistry, Department of Pathophysiological and Therapeutic Sciences, Tottori University Faculty of Medicine, Yonago, Japan.
Naoko
N
Tajima
Division of Medical Biochemistry, Department of Pathophysiological and Therapeutic Sciences, Tottori University Faculty of Medicine, Yonago, Japan.
Yosuke
Y
Horikoshi
Division of Medical Biochemistry, Department of Pathophysiological and Therapeutic Sciences, Tottori University Faculty of Medicine, Yonago, Japan; Division of Anesthesiology and Critical Care Medicine, Department of Surgery, Tottori University Faculty of Medicine, Yonago, Japan.
Masato
M
Nakasone
Division of Medical Biochemistry, Department of Pathophysiological and Therapeutic Sciences, Tottori University Faculty of Medicine, Yonago, Japan; Division of Surgical Oncology, Department of Surgery, Tottori University Faculty of Medicine, Yonago, Japan.
Takehiko
T
Hanaki
Division of Medical Biochemistry, Department of Pathophysiological and Therapeutic Sciences, Tottori University Faculty of Medicine, Yonago, Japan.
Kouki
K
Kamizaki
Division of Medical Biochemistry, Department of Pathophysiological and Therapeutic Sciences, Tottori University Faculty of Medicine, Yonago, Japan.
Tatsuya
T
Matsura
D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects*; D047629:Estrogen Receptor beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D040081:Protein Array Analysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D024508:Tocotrienols / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000975:Antioxidants; D047629:Estrogen Receptor beta; D034741:RNA, Small Interfering; D024508:Tocotrienols; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
Akt; Caveolin; Estrogen receptor; PI3K; Parkinson's disease; Vitamin E