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G2-phase arrest through p21(WAF1 / Cip1) induction and cdc2 repression by gnidimacrin in human hepatoma HLE cells

Mitsuzi Yoshida1, Yuki Matsui, Akira Iizuka

  • 1National Cancer Center Research Institute, Tokyo 104-0045, Japan.

Anticancer Research
|May 6, 2009
PubMed

Insights

Gnidimacrin activates protein kinase C (PKC), restoring sensitivity in resistant cancer cells. This leads to cell cycle arrest by inhibiting cdc2 and inducing p21(WAF1/Cip1).

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Pharmacology

Background:

  • Gnidimacrin exhibits antiproliferative effects on human tumor cell lines.
  • Gnidimacrin functions by binding to and activating protein kinase C (PKC).
  • Human hepatoma HLE cells lacking p53 function and retinoblastoma protein (Rb) expression are resistant to gnidimacrin.

Purpose of the Study:

  • To investigate the mechanism of gnidimacrin's antiproliferative activity in resistant cancer cells.
  • To elucidate the role of protein kinase C (PKC) betaII in mediating gnidimacrin sensitivity.
  • To understand the downstream signaling pathways involved in gnidimacrin-induced cell cycle arrest.

Main Methods:

  • Transfection of HLE cells with PKC betaII gene to create sensitive HLE/PKC betaII cells.
  • Treatment with gnidimacrin and MEK1/2 inhibitor U0126.
  • Analysis of cell cycle progression, protein expression (p21(WAF1/Cip1), cdc2), and transcription factor translocation (E2F-4).

Main Results:

  • HLE/PKC betaII cells demonstrated sensitivity to gnidimacrin, unlike parental HLE cells.
  • Gnidimacrin induced G(2)-phase cell cycle arrest and cdc2 inhibition in HLE/PKC betaII cells.
  • p21(WAF1/Cip1) induction and subsequent cdc2 reduction were observed, dependent on MEK1/2 signaling. E2F-4 nuclear translocation was also noted.

Conclusions:

  • Gnidimacrin overcomes resistance in cancer cells by activating PKC betaII.
  • The drug induces cell growth inhibition via p21(WAF1/Cip1)-dependent cdc2 suppression and transcriptional downregulation.
  • E2F-4 involvement in gnidimacrin-mediated cdc2 suppression suggests a complex regulatory mechanism.

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