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Protease inhibitor TPCK represses Ha-ras (Val12) transformation and nuclear factor-kappa B activation

N Denko1, E Chen, K Laderoute

  • 1STANFORD UNIV,MED CTR,DEPT RADIAT ONCOL,MAYER CANC BIOL RES LABS,STANFORD,CA 94305. SRI INT,DIV LIFE SCI,MENLO PK,CA 94025. UNIV CINCINNATI,SCH MED,DEPT ANAT CELL BIOL & NEUROBIOL,CINCINNATI,OH 45267.

International Journal of Oncology
|May 3, 2011
PubMed

Insights

Certain protease inhibitors like TPCK block cancer cell growth by inhibiting NF-kappa B (nuclear factor kappa B) activity. This study reveals NF-kappa B

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Certain protease inhibitors, such as TPCK, demonstrate anti-tumorigenic effects through mechanisms not fully understood.
  • Nuclear factor kappa B (NF-kappa B) is a family of transcription factors inducible in cells and is a potential target for TPCK in transformed cells.

Purpose of the Study:

  • To investigate the physiological role of NF-kappa B in Ha-ras-induced cell transformation.
  • To differentiate the effects of TPCK on NF-kappa B from its effects on AP-1, another downstream effector of Ha-ras.

Main Methods:

  • Utilized a conditionally transformed NIH3T3 cell line to study Ha-ras transformation.
  • Employed TPCK and TLME as protease inhibitors.
  • Assessed anchorage-independent and anchorage-dependent cell growth.
  • Measured DNA synthesis.
  • Performed gel shift analysis and reporter gene expression assays to evaluate transcriptional activity.

Main Results:

  • TPCK inhibited the anchorage-independent growth of Ha-ras transformed cells, but not anchorage-dependent growth.
  • TPCK reduced Ha-ras-stimulated DNA synthesis in growth factor-depleted cells.
  • TPCK blocked Ha-ras-induced NF-kappa B transcriptional activity.
  • TPCK had minimal impact on Ha-ras-induced AP-1 activity.

Conclusions:

  • TPCK inhibits the transformed phenotype induced by Ha-ras.
  • The anti-tumorigenic mechanism of TPCK involves the inhibition of NF-kappa B transcriptional activity.
  • TPCK's effects are specific to NF-kappa B, with limited impact on AP-1 activity.

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