Differential effects of low and high doses of Taxol in anaplastic thyroid cancer cells: possible implication of the Pin1 prolyl isomerase.
OBJECTIVE
To study the molecular mechanisms of dose-dependent effects of an anticancer drug, Taxol, on the cell cycle machinery and apoptosis-related proteins in thyroid anaplastic cancer cell lines ARO and KTC-2.


METHODS
Western blot analysis was used for the detection of various proteins and of their phosphorylated forms.


RESULTS
Low dose of Taxol that cause apoptosis (25 nM) enhanced Rb protein phosphorylation, decreased the expression of cyclin-dependent kinase inhibitors p27(KIP1) and p21(WAF1) , and potentiated the accumulation of phosphorylated p53 and of the prolyl isomerase Pin1. High Taxol doses (100 and 1000 nM) that cause necrosis-like cell death drastically decreased Pin1 level in both cell lines.


CONCLUSIONS
Low doses of Taxol promoted G(1)/S transition, thus exhibiting mitogen-like effect. Drug-induced Pin1 accumulation could probably facilitate this transition and in parallel contribute to apoptosis via the p53/p73-dependent mechanism. At higher doses of Taxol, there was a dramatic decrease of Pin1 levels which may be a reason for G(2)/M cell cycle arrest.
Pushkarev
V M
VM
V.P. Komisarenko Institute of Endocrinology & Metabolism, AMS of Ukraine, Kyiv, Ukraine. endo@i.kiev.ua
Starenki
D V
DV
Saenko
V A
VA
Pushkarev
V V
VV
Kovzun
O I
OI
Tronko
M D
MD
Popadiuk
I D
ID
Yamashita
S
S
D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009336:Necrosis; D017239:Paclitaxel / Q000008:administration & dosage*; D019696:Peptidylprolyl Isomerase / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D016160:Retinoblastoma Protein / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D050759:Cyclin-Dependent Kinase Inhibitor p21; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D050760:Cyclin-Dependent Kinase Inhibitor p27; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; D017239:Paclitaxel