Impact of the cyclin-dependent kinase inhibitor p27(Kip1) on resistance of tumor cells to anticancer agents

Brad St. Croix, Vivi Ann Flørenes, Janusz W. Rak, Mike Flanagan, Nandita Bhattacharya, Joyce M. Slingerland, Robert S. Kerbel

Research output: Contribution to journalArticlepeer-review

299 Scopus citations

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 p27(Kip1), 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.

Original languageEnglish (US)
Pages (from-to)1204-1210
Number of pages7
JournalNature medicine
Volume2
Issue number11
DOIs
StatePublished - Nov 1996
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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