Impact of the cyclin-dependent kinase inhibitor p27Kip1 on resistance of tumor cells to anticancer agents

Nat Med. 1996 Nov;2(11):1204-10. doi: 10.1038/nm1196-1204.

Abstract

A low proliferating fraction in solid tumors limits the effectiveness of cell cycle-dependent chemotherapeutic agents. To understand the molecular basis of such "kinetic" resistance we cultured tumor cells as multicellular spheroids and examined levels of p27Kip1, a cyclin-dependent kinase inhibitor known to be upregulated by intercellular contact in normal cells. When transferred from monolayer to three-dimensional culture, a consistent upregulation (up to 15-fold) of p27 protein was observed in a panel of mouse and human carcinoma cell lines. Antisense-oligonucleotide-mediated downregulation of p27 in EMT-6 mammary tumor cell spheroids reduced intercellular adhesion, increased cell proliferation, sensitized tumor cells to 4-hydroperoxycyclophosphamide, and restored drug- or radiation-induced cell-cycle perturbations repressed in spheroid culture. Our results implicate p27 as a regulator of drug resistance in solid tumors and suggest that tumor-targeted p27 antagonists may be useful chemosensitizers in conjunction with conventional anticancer therapy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents, Alkylating / pharmacology*
  • Cell Adhesion
  • Cell Cycle Proteins*
  • Cell Division
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclin-Dependent Kinase Inhibitor p27
  • Cyclin-Dependent Kinases / antagonists & inhibitors*
  • Cyclins / metabolism*
  • Drug Resistance, Neoplasm*
  • Humans
  • Mice
  • Microtubule-Associated Proteins / metabolism*
  • Spheroids, Cellular / metabolism
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins*

Substances

  • Antineoplastic Agents, Alkylating
  • CDKN1A protein, human
  • Cdkn1a protein, mouse
  • Cdkn1b protein, mouse
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Microtubule-Associated Proteins
  • Tumor Suppressor Proteins
  • Cyclin-Dependent Kinase Inhibitor p27
  • Cyclin-Dependent Kinases