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Biologic sequelae of interleukin-6 induced PI3-K/Akt signaling in multiple myeloma

T Hideshima1, N Nakamura, D Chauhan

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

Oncogene
|October 11, 2001
PubMed

Insights

Interleukin-6 (IL-6) signaling activates phosphatidylinositol-3 kinase/Akt kinase (PI3-K/Akt) in multiple myeloma (MM) cells. This pathway promotes MM cell growth and survival, while protecting against Dexamethasone-induced apoptosis.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Interleukin-6 (IL-6) is crucial for multiple myeloma (MM) cell growth and survival.
  • IL-6 activates MEK/MAPK and JAK/STAT pathways, and protects against Dexamethasone (Dex)-induced apoptosis via SHP2.
  • The role of IL-6 in activating phosphatidylinositol-3 kinase/Akt kinase (PI3-K/Akt) signaling in MM remains to be fully characterized.

Purpose of the Study:

  • To investigate the role of IL-6 triggered PI3-K/Akt signaling in human multiple myeloma (MM) cells.
  • To elucidate the mechanisms by which IL-6 confers protection against Dexamethasone (Dex)-induced apoptosis.
  • To determine the impact of PI3-K/Akt signaling on MM cell proliferation and cell cycle regulation.

Main Methods:

  • Utilized MM.1S MM cells for experimental analysis.
  • Investigated IL-6 induced Akt/PKB phosphorylation and its downstream targets.
  • Employed the PI3-K inhibitor LY294002 to assess the role of PI3-K/Akt signaling.
  • Analyzed caspase activation, FKHR inactivation, and cell cycle regulatory protein expression.

Main Results:

  • IL-6 induced time- and dose-dependent Akt/PKB phosphorylation and activation of downstream targets in MM.1S cells.
  • Inhibition of Akt by LY294002 partially blocked IL-6-mediated MEK/MAPK activation and proliferation, indicating cross-talk.
  • IL-6 activated PI3-K, associated with SHP2, inactivated caspase-9, and protected against Dex-induced apoptosis, effects abrogated by LY294002.
  • IL-6-induced PI3-K/Akt signaling inactivated FKHR, promoting G1/S phase transition; LY294002 blocked this, leading to p27(KIP1) upregulation and G1 arrest.

Conclusions:

  • PI3-K/Akt signaling is a key mediator of IL-6's pro-survival and proliferative effects in multiple myeloma.
  • IL-6 protects MM cells from Dexamethasone-induced apoptosis by activating PI3-K/Akt signaling, which inactivates caspase-9.
  • IL-6-induced PI3-K/Akt signaling regulates MM cell cycle progression through FKHR inactivation and subsequent G1/S transition.

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