Hypoxia-inducible transcription factor (HIF)-1 alpha stabilization by actin-sequestering protein, thymosin beta-4 (TB4) in Hela cervical tumor cells

Cancer Lett. 2008 Jun 8;264(1):29-35. doi: 10.1016/j.canlet.2008.01.004. Epub 2008 Feb 12.

Abstract

Thymosin beta-4 (TB4) is an actin-sequestering protein to control cytoskeletal reorganization. Here, we investigated whether TB4 proteins (TB4P) affect tumor microenvironment by measuring hypoxia-inducible transcription factor (HIF)-1 alpha stabilization in cervical tumor cells, since TB4P reduced paclitaxel-induced cell death rate. TB4P increased HIF-1 alpha stabilization and transactivation, which is measured by the increase of hypoxia response element (HRE)-luciferase activity and target gene, vascular endothelial growth factor (VEGF) transcription. TB4P also elevated ERK phosphorylation. PD98059, ERK inhibitor reduced HIF-1 alpha increased by TB4P. Paclitaxel-induced cell death was inhibited by hypoxia conditioning that increased HIF-1 alpha stabilization and ERK phosphorylation. PD98059 reversed paclitaxel-induced cell death which was attenuated by hypoxia. Collectively, TB4P could lead tumor cell microenvironment to hypoxia condition, which might be resulted in antitumor drug-resistance induction. It suggests that soluble TB4P could be a novel target to control tumor cell death by regulating tumor cell microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism*
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Blotting, Western
  • Cell Hypoxia
  • Cell Survival / drug effects
  • Drug Resistance, Neoplasm
  • Extracellular Signal-Regulated MAP Kinases / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • HeLa Cells
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / drug effects*
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Paclitaxel / pharmacology
  • Phosphorylation / drug effects
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Thymosin / metabolism
  • Thymosin / pharmacology*
  • Uterine Cervical Neoplasms / drug therapy
  • Uterine Cervical Neoplasms / metabolism*

Substances

  • Actins
  • Antineoplastic Agents, Phytogenic
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • thymosin beta(4)
  • Thymosin
  • Extracellular Signal-Regulated MAP Kinases
  • Paclitaxel