or small interfering RNA signiﬁcantly enhanced the apoptotic
response of various cell types to proteasome inhibition
(Meriin et al., 1998; Robertson et al., 1999; Mitsiades et al.,
2002; Chauhan et al., 2003; Hideshima et al., 2004; Small
et al., 2004; Wang et al., 2008). Evaluation of the mechanisms
underlying induction of these anti-apoptotic molecules may
contribute to the development of improved therapies using
In the current study, we investigated the role of MAPKs in the
induction of BAG3 by MG132. Our data showed that p38 and
ERK inhibitors had little effect on the induction of BAG3 by
MG132 but that inhibition of JNK signiﬁcantly reduced BAG3
expression by MG132. Several earlier studies have looked at the
effects of bortezomib or MG132 treatment on molecular sig-
nalling in different cancer types. In liver, breast and pancreatic
cancer cells treated with a proteasome inhibitor, JNK and ERK
showed very similar patterns of activation to those described
here in kidney cancer cells (Yang et al., 2004; Codony-Servat
et al., 2006; Lauricella et al., 2006; Sloss et al., 2008).
The JNK pathway has been associated with the induction of
apoptosis in response to various cellular stresses such as treat-
ment with anti-cancer drugs. We did not expect JNK activa-
tion to be involved in BAG3 induction and that inhibition of
JNK activation would enhance apoptotic responses of kidney
cancer cells to proteasome inhibition. Meriin et al. (1998) had
suggested that the proteasome inhibitor-induced JNK activa-
tion would be pro-apoptotic in lymphoid tumours. However,
a growing body of evidence suggests that JNK activation is
also central to anti-apoptotic and growth-promoting effects.
For instance, JNK has been shown to be activated and/or
overexpressed in an anti-apoptotic manner in various cancers,
and JNK inhibition has been shown to increase anti-cancer
effects of proteasome inhibitors in pancreatic cancer cells,
suggesting an anti-apoptotic role for JNK in this cell type
(Malicet et al., 2003; Li et al., 2007; Sloss et al., 2008). The JNK
pathway is also reported to be involved in the activation of
Hsp70 (Kim et al., 2005), one of whose most important func-
tions is to prevent apoptosis. Although the reported results to
date may seem contradictory, they may more likely represent
tissue and cell type-speciﬁc differences in the response to
In the current study, our data showed that the JNK pathway
was related to the activation of BAG3 expression in kidney
cancer cells. These data indicate that the JNK pathway might
play opposing roles in the induction of cellular apoptosis and
maintenance of cellular homeostasis, suggesting that JNK
triggers and signals to cellular apoptosis, as well as to the
pathways leading to the cell survival.
This work was supported by National Natural Science Foun-
dation of China (30870522) and Shenyang Outstanding
Talent Foundation to H-Q.W.
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Induction of BAG3 by MG132 via JNK
H-Q Wang et al
British Journal of Pharmacology (2009) 158 1405–1412