Altered levels and regulation of stathmin in paclitaxel-resistant ovarian cancer cells.
Two paclitaxel(Ptx)-resistant ovarian cancer cell lines, 1A9/Ptx-10 and 1A9/Ptx-22, isolated from the 1A9 cell line (a clone of the A2780 line) by continuous exposure to Ptx and verapamil, have point mutations in their major beta-tubulin gene and in one or both alleles of their TP53 gene. These cells were examined for alterations in cell cycle regulators and the tubulin-binding protein stathmin. Unlike parental cells, neither 1A9/Ptx-10 nor 1A9/Ptx-22 expressed detectable levels of p21(WAF1/Cip1), a putative transcriptional regulator of stathmin, but did overexpress stathmin and Bcl2. No differences were noted in the expression levels of proliferative cell nuclear antigen or tyrosine-phosphorylated p34Cdc2. Ptx treatment altered little the expression of stathmin in the parental cell line, although it increased p21(WAF1/Cip1) levels several-fold. Infection of Ptx-resistant lines with a wild-type TP53-bearing adenovirus (AdWTp53) changed cell cycle distribution and increased the levels of p21(WAF1/Cip1), but caused no changes in stathmin levels. Microtubule drug resistance in ovarian carcinoma may be associated with altered p53/21(WAF1/Cip1) regulatory pathways for stathmin expression and function.
Balachandran
Raghavan
R
Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Welsh
Manda J
MJ
Day
Billy W
BW
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008868:Microtubule Proteins; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics*; D050777:Stathmin
D000972:Antineoplastic Agents, Phytogenic; D008868:Microtubule Proteins; D010750:Phosphoproteins; C493995:STMN1 protein, human; D050777:Stathmin; D017239:Paclitaxel