Low concentrations of paclitaxel induce cell type-dependent p53, p21 and G1/G2 arrest instead of mitotic arrest: molecular determinants of paclitaxel-induced cytotoxicity

Citation
P. Giannakakou et al., Low concentrations of paclitaxel induce cell type-dependent p53, p21 and G1/G2 arrest instead of mitotic arrest: molecular determinants of paclitaxel-induced cytotoxicity, ONCOGENE, 20(29), 2001, pp. 3806-3813
Citations number
56
Categorie Soggetti
Onconogenesis & Cancer Research
Journal title
ONCOGENE
ISSN journal
09509232 → ACNP
Volume
20
Issue
29
Year of publication
2001
Pages
3806 - 3813
Database
ISI
SICI code
0950-9232(20010628)20:29<3806:LCOPIC>2.0.ZU;2-7
Abstract
Paclitaxel (PTX), a microtubule-active agent, blocks cell proliferation by inhibiting mitotic progression leading to mitotic and postmitotic arrest an d cell death. Here we demonstrate for the first time that very low concentr ations of PTX (3-6 nM) can completely inhibit cell proliferation without ar resting cells at mitosis, At these low concentrations that are insufficient to inhibit mitotic progression, PTX induced both p53 and p21 causing CI an d G2 arrest in A549. In contrast, low PTX concentrations failed to induce G 1 and G2 arrest in A549/E6 cells, that do not express p53, Furthermore, we observed that the levels of p53 and p21 induced by adriamycin and by low co ncentrations of PTX in A549 cells were comparable. This observation led us to conclude that tow concentrations of PTX can induce p53 and p21 sufficien tly to cause G1 and G2, Many other cell lines, including HCT116 cells, do n ot readily upregulate p53 in response to PTX, and therefore undergo exclusi vely mitotic and postmitotic arrest after PTX treatment. At low concentrati ons that do not cause mitotic arrest, PTX did not significantly inhibit pro liferation of these cells. In HCT116 cells, loss of p53 (HCT/p53(-/-)) or p 21 (HCT/p21(-/-)) affects both Bar and Bcl-2 expression. In cells lacking p 53, levels of Bar and p21 were decreased. In cells lacking p21, levels of w t p53 were highly increased to compensate for the loss of p21, This in turn results in upregulation of Bar and downregulation of Bcl-2 resulting in an increase of the apoptotic Bax/Bcl2 ratio consistent with increased sensiti vity of these cells to apoptotic stimuli, High levels of p53 and Bax/Bcl-2 ratio can also explain why loss of p21 is rarely found in human cancer.