Overexpression of p21(waf1) leads to increased inhibition of E2F-1 phosphorylation and sensitivity to anticancer drugs in retinoblastoma- negative human sarcoma cells

W. Li, J. Fan, D. Hochhauser, J. R. Bertino

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39 Scopus citations

Abstract

The effect of overexpression of p21(waf1) on drug sensitivity was studied in an osteosarcoma cell line (SaOs-2) lacking both p53 and functional retinoblastoma protein using a tetracycline (TC)-inducible expression system. p21(waf1) expression was barely detectable in SaOS-2 cells incubated in the presence of TC. After TC withdrawal, high levels of p21(waf1) were induced in these cells. These p21(waf1)-induced cells showed increased sensitivity to doxorubicin, tomudex, and methotrexate as compared to uninduced cells; this condition is associated with increased apoptosis. Expression of p21(waf1) reduced cyclin A-associated kinase activity and, surprisingly, resulted in inhibition of phosphorylation of E2F-1 and increased E2F-1 binding activity. An S-G2 cell cycle arrest/delay and an increase in expression of E2F- responsive genes (dihydrofolate reductase and thymidylate synthase) was correspondingly observed. Overexpression of p21(waf1) in cells lacking functional retinoblastoma protein may mediate sensitivity to anticancer drugs by inhibiting E2F-1 phosphorylation, which may contribute to increased S-G2 cell cycle delay and increased cell susceptibility to apoptosis.

Original languageEnglish (US)
Pages (from-to)2193-2199
Number of pages7
JournalCancer Research
Volume57
Issue number11
StatePublished - 1997

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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