alpha-Synuclein stimulates differentiation of osteosarcoma cells: relevance to down-regulation of proteasome activity.
Because a limited study previously showed that alpha-synuclein (alpha-syn), the major pathogenic protein for Parkinson disease, was expressed in differentiating brain tumors as well as various peripheral cancers, the main objective of the present study was to determine whether alpha-syn might be involved in the regulation of tumor differentiation. For this purpose, alpha-syn and its non-amyloidogenic homologue beta-syn were stably transfected to human osteosarcoma MG63 cell line. Compared with beta-syn-overexpressing and vector-transfected cells, alpha-syn-overexpressing cells exhibited distinct features of differentiated osteoblastic phenotype, as shown by up-regulation of alkaline phosphatase and osteocalcin as well as inductive matrix mineralization. Further studies revealed that proteasome activity was significantly decreased in alpha-syn-overexpressing cells compared with other cell types, consistent with the fact that proteasome inhibitors stimulate differentiation of various osteoblastic cells. In alpha-syn-overexpressing cells, protein kinase C (PKC) activity was significantly decreased, and reactivation of PKC by phorbol ester significantly restored the proteasome activity and abrogated cellular differentiation. Moreover, activity of lysosome was up-regulated in alpha-syn-overexpressing cells, and treatment of these cells with autophagy-lysosomal inhibitors resulted in a decrease of proteasome activity associated with up-regulation of alpha-syn expression, leading to enhance cellular differentiation. Taken together, these results suggest that the stimulatory effect of alpha-syn on tumor differentiation may be attributed to down-regulation of proteasome, which is further modulated by alterations of various factors, such as protein kinase C signaling pathway and a autophagy-lysosomal degradation system. Thus, the mechanism of alpha-syn regulation of tumor differentiation and neuropathological effects of alpha-syn may considerably overlap with each other.
Fujita
Masayo
M
Laboratory for Chemistry and Metabolism, Tokyo Metropolitan Institute for Neuroscience, Fuchu, Tokyo 183-8526, Japan .
Sugama
Shuei
S
Nakai
Masaaki
M
Takenouchi
Takato
T
Wei
Jianshe
J
Urano
Tomohiko
T
Inoue
Satoshi
S
Hashimoto
Makoto
M
D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D001932:Brain Neoplasms / Q000201:enzymology / Q000235:genetics / Q000648:ultrastructure; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D010006:Osteoblasts / Q000378:metabolism* / Q000648:ultrastructure; D012516:Osteosarcoma / Q000201:enzymology* / Q000235:genetics / Q000648:ultrastructure; D010703:Phorbol Esters / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000096:biosynthesis* / Q000235:genetics; D011493:Protein Kinase C / Q000378:metabolism; D051844:alpha-Synuclein / Q000096:biosynthesis* / Q000235:genetics; D051846:beta-Synuclein / Q000096:biosynthesis / Q000235:genetics
D009363:Neoplasm Proteins; D010703:Phorbol Esters; D051844:alpha-Synuclein; D051846:beta-Synuclein; D011493:Protein Kinase C; D046988:Proteasome Endopeptidase Complex