Cheleritrine inibe IGFBP-5 e provoca aumento da adesão e diminuição da sobrevida em células
Hs578T do câncer de mama
Cheleritrine: Inibe as 12 isoformas da Proteína Kinase C (PKC). A ativação da PKC possui
papel central na transdução de sinais envolvendo a proliferação e a diferenciação celular
assim como a apoptose, Inibe polimerização da actina / tubulina,Inibe Endotelina-1,Diminui
potencial de membrana mitocondrial (Delta-Psimt),Inibe ciclinas A,B, CDK1,CDK2 e ativa p27:
pára ciclo celular em G2/M,Inibe NHE1e anidrase carbônica e acidifica citoplasma, Inibe DHLA : inibe glicólise anaeróbia e ativa fosforilação oxidativa, Inibe HIF-1, Inibe NF-kappaB,
Atenua efluxo da taurina : efeito estruturador do protoplasma, Ativa sistema imune:
aumenta número e atividade dos linfócitos T, aumenta atividade e número das células
dendríticas e das “Natural Killer”, aumenta função dos macrófagos, aumenta IL-2 e
Interferon – gama, Impede mudança estrutural da piruvato kinase tetramérica para dimérica
: PKM2, Inibe vários fatores de crescimento incluindo EGF (Epidermal Growth Factor), Inibe
Ras/Raf-1/MEK1,2/ERK1,2, Inibe ERKs/JNK/MAPK, Inibe a via de sinalização PI3K/AKT ,
Bloqueia OrfaninFG/Nociceptina e restabelece efeito analgésico da morfina, Inibe expressão
do Bcl-X(L): anti-apoptótico crucial na hipóxia, Inibe IGFBP-5 e aumenta adesão e diminui a
sobrevida neoplásica, Anti-angiogênico, Baixa dose: apoptose, Alta dose: parada do ciclo
celular em G2/M, Antiproliferativo,Aumenta a diferenciação celular, etc...José de Felippe
Junior
Signalling pathways involved in the
direct effects of IGFBP-5 on breast
epithelial cell attachment and survival.
McCaig C, Perks CM, Holly JM.
J Cell Biochem. 2002;84(4):784-94.
Source
Division of Surgery, Department of Hospital Medicine, Bristol Royal Infirmary, Bristol,
BS2 8HW, England, United Kingdom. [email protected]
Abstract
We have demonstrated previously that IGFBP-5 can confer survival against apoptosis
induced by ceramide, C2, or a small synthetic arginine-glycine-aspartic acid (RGD)containing peptide in a direct manner. The endogenous ceramide-induced pathway is
normally counter-balanced by survival signals mediated by sphingosine kinase (SK) and
protein kinase C (PKC). In order to investigate whether these pathways are involved in
the IGFBP-5 survival effect, we have used inhibitors of SK (N, N-di-methyl
sphingosine, DMS) and PKC (chelerythrine chloride, CC). The effect of pre-incubating
Hs578T breast cancer cells with IGFBP-5 on cell adhesion or on subsequent cell death
induced by C2 or RGD was investigated with and without the presence of DMS or CC.
Cell death was determined by trypan blue cell counts and apoptosis confirmed by
morphological assessment and flow cytometry. Cell attachment was determined by a
cell adhesion assay. The presence of IGFBP-5 significantly inhibited cell death induced
by C2 or RGD, compared to the triggers of apoptosis alone (P<0.01 in both cases). In
the presence of either IGFBP-5, CC or DMS, there was no significant effect on cell
death compared to the control. IGFBP-5 in the presence of either inhibitor resulted in a
significant increase in cell death; IGFBP-5 also lost its ability to confer survival on C2
and RGD-induced apoptosis and in contrast significantly increased cell death. In the cell
adhesion assay, IGFBP-5 significantly increased cell attachment over basal levels. In
the presence of either inhibitor the IGFBP-5 effect on cell adhesion was reversed and
cell attachment was reduced to below basal levels. These data suggest that IGFBP-5
promotes the attachment and survival of Hs578T cells by modulating the balance
between ceramide and opposing survival signals.
Copyright 2002 Wiley‐Liss, Inc.
PMID:11835403