[Neural protective agents, propentofylline (PPF) could induce apoptotic cell death in the human glioma cells: analysis of Bcl-2 and Bax alpha/Bax beta expressions].
In the previous study, we have shown that propentofylline (PPF) could induce the cellular differentiation and apoptosis-related growth regression in the human glioma cell lines. Its biological functions were partly due to the increasing endogeneous NGF and its high affinity receptor, trk A productions. Although little has been known about the precise machinary regulating the propentofylline induced apoptosis. Recently, we have found that propentofylline could modulate some apoptosis related genes products in the glioma cell lines, i.e. NGF, trk A mRNA levels and Fas protein expressions were increased, whereas bcl-2 mRNA level was decreased. In the present study, we examined the apoptotic signal cascade, especially focusing on the expressing pattern of Bcl-2/Bax gene products. In the normal human astrocyte cells, Bax-beta was markedly expressed, whereas Bcl-2 and Bax-alpha proteins and mRNA were weakly or even nondetectable. Accordingly, Bax beta might be a dominant variant in the normal glial cells, which could have the appropriate balance of proapoptotic (Bax beta) and anti-apoptotic proteins (Bcl-2). In the glioma cells, we showed the over-expressions of Bcl-2 and Bax alpha compared with the normal counterparts. According to Bax dominant theory, Bax, not Bcl-2 may have a major role in regulating apoptosis by means of homodimerization. In might be implied that in the glioma cells, excessive expressions of Bcl-2 and Bax alpha would favor the formation of the Bax alpha/Bax beta heterodimer or the Bax beta/Bcl-2 heterodimer rather than the Bax beta/Bax beta homodimer, which might be presumed to be functional proteins. And finally the increasing relative ratio of Bax alpha/ Bax beta or Bax beta/Bcl-2 to Bax beta/Bax beta could allow the tumor cells to survive. Thus over-expression of the bcl-2 and bax alpha gene renders the glioma cells resistant to apoptosis. In the present study, PPF could promote Bax beta over-expression and Bcl-2 retardative expression in the glioma cells, whereas had no effect on Bax alpha expression. Therefore, PPF might promote apoptotic cell death through the mechanism that restore the glioma cells to the appropriate balance of proapoptotic and anti-apoptotic proteins like as normal astrocytes. Our results indicated that propentofylline might have a potential role as apoptotic modulators in the human glioma cell lines, not only its protective activities against neuronal ischemic damages.
Satone
A
A
Department of Neurosurgery, Hokuto Hospital, Hokkaido, Japan.
Ukita
H
H
Murakami
H
H
Chiba
S
S
Oshima
Y
Y
Ogata
A
A
Ikeda
M
M
Yamaguchi
H
H
Matsumoto
A
A
Ide
W
W
Hashimoto
I
I
Kamada
H
H
D017209:Apoptosis; D002455:Cell Division; D002460:Cell Line; D005910:Glioma / Q000473:pathology*; D006801:Humans; D011518:Proto-Oncogene Proteins / Q000032:analysis* / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis* / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D014407:Tumor Cells, Cultured; D014970:Xanthines / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D014970:Xanthines; D051028:bcl-2-Associated X Protein; C032114:propentofylline