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Bone marrow X kinase-mediated signal transduction in irradiated vascular endothelium

Tianxiang Tu1, Dinesh Thotala, Ling Geng

  • 1Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, TN 37232-5671, USA.

Cancer Research
|April 17, 2008
PubMed

Insights

Targeting bone marrow X kinase (Bmx) with inhibitors like LFM-A13 can enhance radiotherapy efficacy. Inhibiting Bmx in endothelial cells and tumor vasculature radiosensitizes them, leading to improved tumor growth delay.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Oncology

Background:

  • Phosphatidyl inositol-3 kinase/Akt pathway activation by radiation requires Akt binding to phosphatidyl-inositol phosphates (PIP).
  • Bone marrow X kinase (Bmx), a tyrosine kinase, also binds PIPs and is involved in cell growth and survival.
  • Bmx signaling in vascular endothelium may contribute to radiation response.

Purpose of the Study:

  • Investigate Bmx signaling in vascular endothelium following ionizing radiation.
  • Determine if Bmx inhibition can radiosensitize endothelial cells and tumor vasculature.
  • Evaluate Bmx as a molecular target for radiosensitizing agents.

Main Methods:

  • Studied Bmx activation in response to ionizing radiation in endothelial cells.
  • Used retroviral shRNA to knock down Bmx protein in human umbilical vascular endothelial cells (HUVECs).
  • Administered Bmx inhibitor LFM-A13 to HUVECs and in mouse lung cancer models.
  • Assessed radiosensitization using clonogenic survival, apoptosis, cell migration, and tubule formation assays.
  • Evaluated tumor microvascular destruction and tumor growth delay in vivo.

Main Results:

  • Bmx was rapidly activated by clinically relevant doses of ionizing radiation.
  • Bmx inhibition enhanced radiosensitization in endothelial cells and tumor vascular endothelium.
  • shRNA knockdown of Bmx and LFM-A13 treatment significantly radiosensitized HUVECs.
  • LFM-A13 combined with radiation caused significant tumor microvascular destruction and enhanced tumor growth delay in mice.

Conclusions:

  • Bmx signaling is activated by ionizing radiation in vascular endothelium.
  • Inhibiting Bmx, a PIP-binding tyrosine kinase, enhances radiotherapy efficacy.
  • Bmx is a promising molecular target for developing novel radiosensitizing agents to improve cancer treatment.

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