Premium
Hyperphosphorylation of tau is mediated by ERK activation during anticancer drug‐induced apoptosis in neuroblastoma cells
Author(s) -
Guise S.,
Braguer D.,
Carles G.,
Delacourte A.,
Briand C.
Publication year - 2001
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/1097-4547(20010201)63:3<257::aid-jnr1019>3.0.co;2-t
Subject(s) - phosphorylation , hyperphosphorylation , apoptosis , mapk/erk pathway , tau protein , microbiology and biotechnology , neurodegeneration , kinase , biology , chemistry , cancer research , medicine , biochemistry , alzheimer's disease , disease
Phosphorylated tau protein is the major component of paired helical filaments in Alzheimer disease (AD). We have previously shown that abnormal tau phosphorylation was induced in neuroblastoma SK‐N‐SH cells by the anticancer drug, paclitaxel, during apoptosis [Guise et al., 1999: Apoptosis 4:47–58]. In the present study, we first demonstrated a shift from fetal tau to hyperphosphorylated tau after incubation with paclitaxel, that showed some similarities with the hyperphosphorylated tau in AD, by using several tau antibodies, N‐Term, Tau‐1 and AT‐8. Tau phosphorylation occurred independently of caspase‐3 activation. We next showed that a sustained activation of ERK (extracellular signal‐regulated kinase) induced both tau phosphorylation and apoptosis during paclitaxel treatment (1 μM). The inhibition of ERK activation by using the pharmacological MEK1/2 inhibitor, PD98059 (50 μM), or an antisense strategy, reduced tau phosphorylation and neuronal apoptosis ( P < 0.001), indicating a link between ERK activation, tau phosphorylation and apoptosis. Doxorubicin (0.2 μM), an anticancer drug whose mechanism of action is independent of microtubules, also induced ERK activation, tau phosphorylation and apoptosis. Moreover, doxorubicin induced some morphological features of neurodegeneration such as loss of neurites and disorganization of the cytoskeleton in apoptotic neuroblastoma cells. Altogether, our results suggest that tau phosphorylation plays a significant role in apoptosis enhancing disruption of microtubules that in turn leads to formation of apoptotic bodies, suggesting that neurodegeneration and apoptosis are related. J. Neurosci. Res. 63:257–267, 2001. © 2001 Wiley‐Liss, Inc.