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Biologic sequelae of c-Jun NH(2)-terminal kinase (JNK) activation in multiple myeloma cell lines

Teru Hideshima1, Toshiaki Hayashi, Dharminder Chauhan

  • 1Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.

Oncogene
|December 4, 2003
PubMed

Insights

Inhibiting c-Jun NH(2)-terminal kinase (JNK) with SP600125 halts multiple myeloma (MM) cell growth and activates NF-kappaB. This JNK inhibition is effective even in MM cells attached to bone marrow stromal cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • c-Jun NH(2)-terminal kinase (JNK) pathway activation is observed with therapeutic treatments.
  • The biological consequences of inhibiting constitutive JNK activation remain unclear.
  • Multiple myeloma (MM) is a cancer of plasma cells.

Purpose of the Study:

  • To investigate the biological effects of inhibiting JNK in multiple myeloma cell lines.
  • To determine the impact of JNK inhibition on MM cell growth, cell cycle, and interaction with bone marrow stromal cells (BMSCs).

Main Methods:

  • Utilized JNK-specific inhibitor SP600125 and IKK-specific inhibitor PS-1145.
  • Assessed MM cell lines (U266, MM.1S) for growth inhibition, cell cycle arrest (G1, G2/M), and protein expression (p27Kip1, p53, JNK).
  • Examined the effects of SP600125 on MM cells co-cultured with BMSCs, and analyzed activation of NF-kappaB, STAT3, Akt, and ERK signaling pathways.

Main Results:

  • SP600125 induced growth inhibition and cell cycle arrest (G1 in U266, G2/M in MM.1S).
  • Exogenous IL-6 or IGF-1 did not overcome SP600125-induced growth inhibition; IL-6 enhanced G2/M arrest.
  • SP600125 inhibited growth of MM cells adherent to BMSCs and dose-dependently activated NF-kappaB via IKKalpha phosphorylation and IkappaBalpha degradation.
  • SP600125 did not affect STAT3, Akt, or ERK phosphorylation; PS-1145 blocked NF-kappaB activation and SP600125's anti-apoptotic effect.

Conclusions:

  • JNK inhibition with SP600125 induces growth arrest in multiple myeloma cells.
  • JNK inhibition activates the NF-kappaB pathway in MM cells.
  • Targeting JNK may represent a therapeutic strategy for multiple myeloma, potentially through modulation of NF-kappaB signaling.

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