Involvement of ERK1/2 and p38 MAP kinase in doxorubicin-induced uPA expression in human RC-K8 lymphoma and NCI-H69 small cell lung carcinoma cells

Masami Niiya, Kenji Niiya, Misako Shibakura, Noboru Asaumi, Chikamasa Yoshida, Katsuji Shinagawa, Takanori Teshima, Fumihiko Ishimaru, Kazuma Ikeda, Mitsune Tanimoto

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

Abstract

We previously demonstrated the doxorubicin-induced urokinase-type plasminogen activator (uPA) expression in human RC-K8 lymphoma cells and NCI-H69 small cell lung carcinoma cells in which reactive oxygen species might be involved. Western blotting analysis revealed phosphorylation/activation of mitogen-activated protein (MAP) kinases, such as extracellular signal-regulated kinase (ERK) 1/2, p38 MAP kinase and stress-activated protein kinase/c-jun N-terminal protein kinase (SAPK/JNK) in doxorubicin-treated RC-K8 and H69 cells, and, therefore, we attempted to identify the MAP kinases implicated in doxorubicin-induced uPA expression by the use of their specific inhibitors. U0126, SB202190 and JNKI-1, inhibitors for MAPK kinase, (MEK) 1/2, p38 MAP kinase and SAPK/JNK, respectively, specifically and clearly inhibited their corresponding kinases. U0126 and SB202190, but not JNKI-1, almost completely inhibited the doxorubicin-induced uPA expression in both RC-K8 and H69 cells. However, U0126 rather enhanced the doxorubicin-induced activation of caspase-3 and poly ADP-ribose polymerase (PARP), and U0126 itself activated caspase-3 and PARP. Interestingly, JNKI-1 inhibited the doxorubicin-induced activation of caspase-3 and PARP. Therefore, doxorubicin treatment activates the above three kinases, but different MAP kinase signaling is responsible in the doxorubicin-induced caspase activation and expression of uPA. Thus, we could possibly manipulate the direction of doxorubicin-induced MAP kinase activation and the effects of doxorubicin on the tumor cell biology by the use of MAP kinase inhibitors.

Original languageEnglish
Pages (from-to)310-319
Number of pages10
JournalOncology
Volume67
Issue number3-4
DOIs
Publication statusPublished - 2004

Keywords

  • Apoptosis
  • Caspase
  • Doxorubicin
  • Human lymphoma cells
  • Mitogen-activated protein (MAP) kinase
  • Small cell lung carcinoma (SCLC) cells
  • Urokinase-type plasminogen activator (uPA)

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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