Molecular determinants of UCN-01-induced growth inhibition in human lung cancer cells

Int J Cancer. 2000 Jan 15;85(2):275-80. doi: 10.1002/(sici)1097-0215(20000115)85:2<275::aid-ijc20>3.0.co;2-5.

Abstract

UCN-01 (7-hydroxystaurosporine) inhibits the growth of various malignant cell lines in vitro and in vivo. In this study, a human small cell lung carcinoma subline resistant to UCN-01, SBC-3/UCN, was established and characterized. SBC-3/UCN cells showed 8-fold greater resistance to the UCN-01-induced growth-inhibitory effect than the parent cells, SBC-3. No UCN-01-induced G1 accumulation in SBC-3 cells was observed in SBC-3/UCN cells and decreased expression of phosphorylated RB protein was found in SBC-3 cells. Neither basal expression nor induction of p21(Cip1) by UCN-01 treatment was detected in the SBC-3/UCN cell line. An inhibitory effect of UCN-01 on CDK2 activity, which is mediated by p21(Cip1)/CDK2 complex formation upon UCN-01 treatment, was observed in SBC-3 but not in SBC-3/UCN cells. SBC-3/UCN showed higher CDK6 activity than SBC-3 cells. UCN-01 did not inhibit the CDK4 and CDK6 activities in both cells. We screened the cell cycle regulatory molecules associated with G(1)/S progression and found a remarked decrease in interferon regulatory factor 1 (IRF-1), which is known to cooperate with p53 in p21(Cip1) induction. Our results suggest that p21(Cip1) regulation via the IRF-1-associated pathway may represent a major determinant of UCN-01-induced growth inhibition in human lung cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaloids / pharmacology*
  • Antineoplastic Agents / pharmacology*
  • CDC2-CDC28 Kinases*
  • Cell Cycle / drug effects
  • Cell Division / drug effects
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclin-Dependent Kinases / metabolism
  • Cyclins / metabolism
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / pathology
  • Protein-Serine-Threonine Kinases / metabolism
  • Retinoblastoma Protein / drug effects
  • Retinoblastoma Protein / metabolism
  • Staurosporine / analogs & derivatives
  • Tumor Cells, Cultured

Substances

  • Alkaloids
  • Antineoplastic Agents
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Enzyme Inhibitors
  • Retinoblastoma Protein
  • 7-hydroxystaurosporine
  • Protein-Serine-Threonine Kinases
  • CDC2-CDC28 Kinases
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases
  • Staurosporine