Paclitaxel induces inactivation of p70 S6 kinase and phosphorylation of Thr421 and Ser424 via multiple signaling pathways in mitosis

Xiao Feng Le, Walter N. Hittelman, Jiaxin Liu, Amanda McWatters, Chun Li, Gordon B. Mills, Robert C. Bast

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

The 70kDa ribosomal S6 kinase (p70S6K) is important for cell growth and survival. Activation of p70S6K requires sequential phosphorylation of multiple serine and threonine sites often triggered by growth factors and hormones. Here, we report that paclitaxel, a microtubule-damaging agent, induces phosphorylation of p70S6K at threonine 421 and serine 424 (T421/S424) in a concentration- and time-dependent manner in multiple breast and ovarian cancer cell lines demonstrated by a T421/S424 phospho-p70S6K antibody. Phosphoamino-acid analysis and Western blot analysis by serine-/threonine-specific antibodies further confirms that both serine and threonine residues are phosphorylated in p70S6K following treatment with paclitaxel. Paclitaxel-induced p70S6KT421/S424 phosphorylation requires both de novo RNA and protein synthesis via multiple signaling pathways including ERK1/2 MAP kinase, JNK, PKC, Ca++, PI3K, and mammalian target of rapamycin (mTOR). Despite phosphorylation of p70S6KT421/S424, paclitaxel inactivates this kinase in a concentration- and time-dependent manner as illustrated by in vitro kinase assay. Inhibitors of mTOR, PI3K, and Ca++ impair p70S6K activity, whereas inhibitors of JNK and PKC stimulate p70S6K activity. Inhibition of PKC and JNK prevents paclitaxel-induced p70S6K inactivation. Moreover, the paclitaxel-induced phosphorylation and low activity of p70S6K mainly occurs during mitosis. In summary, paclitaxel is able to induce p70S6KT421/S424 phosphorylation and decrease its activity in mitotic cells via multiple signaling pathways. Our data suggest that paclitaxel-induced p70S6KT421/S424 phosphorylation and kinase inactivation are differentially regulated. Our data also indicate that paclitaxel may exert its antitumor effect, at least in part, via inhibition of p70S6K.

Original languageEnglish (US)
Pages (from-to)484-497
Number of pages14
JournalOncogene
Volume22
Issue number4
DOIs
StatePublished - Jan 30 2003
Externally publishedYes

Keywords

  • Activation
  • Mitosis
  • P70S6K
  • Paclitaxel
  • Phosphorylation

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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