Overexpression of p21(waf1) decreases G2-M arrest and apoptosis induced by paclitaxel in human sarcoma cells lacking both p53 and functional Rb protein.
We examined the effect of overexpression of p21(waf1) on cytotoxicity of paclitaxel, a microtubule stabilizer, using a tetracycline-inducible expression system in human sarcoma cells (SaOs-2) that lack both functional retinoblastoma protein and p53. Under normal growth conditions, p21(waf1) is not detectable in SaOs-2 cells. Upon p21(waf1) induction by tetracycline withdrawal, we observed a reduced apoptotic response to paclitaxel with a 3- to 6-fold increase in IC50 values compared with that of cells not induced by p21(waf1). We also observed a 5-fold increase in the IC50 value when cytotoxicity to vincristine, another microtubule-disrupting agent, was assessed, whereas we observed a marked decrease in the IC50 value after p21(waf1) induction in response to etoposide, a topoisomerase II inhibitor. After treatment with paclitaxel, less accumulation of G2-M was observed in p21(waf1)-induced cells compared with non-p21(waf1)-induced cells (57% versus 74%). p21(waf1) induction also inhibited the increased cyclin B1-associated kinase activity induced by paclitaxel. Overexpression of p21(waf1) in SaOs-2 cells lacking both p53 and functional retinoblastoma protein may decrease the G2-M arrest induced by paclitaxel due to suppression of the S-G2 checkpoint, resulting in a decreased apoptotic response of cells to paclitaxel.
Li
W
W
Laboratory of Molecular Pharmacology, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Fan
J
J
Banerjee
D
D
Bertino
J R
JR
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology*; D019926:Cyclin B / Q000378:metabolism; D056744:Cyclin B1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000502:physiology*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D016195:G2 Phase / Q000502:physiology; D006801:Humans; D008938:Mitosis / Q000502:physiology; D012516:Osteosarcoma; D017239:Paclitaxel / Q000494:pharmacology*; D016160:Retinoblastoma Protein / Q000235:genetics; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D000972:Antineoplastic Agents, Phytogenic; C534699:CCNB1 protein, human; C493956:CDKN1A protein, human; D019926:Cyclin B; D056744:Cyclin B1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D016203:CDC2 Protein Kinase; D017239:Paclitaxel