Hyperphosphorylation of tau is mediated by ERK activation during anticancer drug-induced apoptosis in neuroblastoma cells

Phosphorylated tau protein is the major component of paired helical filamen ts in Alzheimer disease (AD). We have previously shown that abnormal tau ph osphorylation 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 hype rphosphorylated tau after incubation with paclitaxel, that showed some simi larities with the hyperphosphorylated tau in AD, by using several tau antib odies, N-Term, Tau-l and AT-8, Tau phosphorylation occurred independently o f 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 muM). The inhibition of ERK activ ation by using the pharmacological MEK1/2 inhibitor, PD98059 (50 muM), or a n antisense strategy, reduced tau phosphorylation and neuronal apoptosis (P < 0.001), indicating a link between ERK activation, tau phosphorylation an d apoptosis. Doxorubicin (0.2 <mu>M), an anticancer drug whose mechanism of action is independent of microtubules, also induced ERK activation, tau ph osphorylation and apoptosis. Moreover, doxorubicin induced some morphologic al features of neurodegeneration such as loss of neurites and disorganizati on of the cytoskeleton in apoptotic neuroblastoma cells. Altogether, our re sults suggest that tau phosphorylation plays a significant role in apoptosi s enhancing disruption of microtubules that in turn leads to formation of a poptotic bodies, suggesting that neurodegeneration and apoptosis are relate d. (C) 2001 Wiley-Liss, Inc.