Altered levels and regulation of stathmin in paclitaxel-resistant ovarian cancer cells

Abstract

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 b-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 p34 Cdc2 . 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.

Expression of Stathmin, a Developmentally Controlled Cytoskeleton-Regulating Molecule, in Demyelinating Disorders

“…This role has been highlighted recently by the experiments of Jin et al (2004), who have shown that decreased stathmin levels in these cells inhibit their mobilization from the SVZ. The linkage between stathmin levels and migration is also supported by studies on tumoral cell lines in which stathmin levels correlate with an invasive phenotype (Balachandran et al, 2003;Walter-Yohrling et al, 2003). Our studies in vitro, in cultured oligodendrocyte progenitors, indicate that stathmin is elevated by stimuli favoring migrations (i.e., PDGF and bFGF) (Fig.…”

Chemotherapy Dosing Schedule Influences Drug Resistance Development in Ovarian Cancer

“…Upregulation of the b-tubulinIII isoform, as observed clinically in taxane-resistant ovarian cancer, causes docetaxel resistance by inhibiting taxaneinduced microtubule assembly (23). The action of docetaxel on microtubules is also hindered by stathmin1, a gene found overexpressed in ovarian tumors (44). Stathmin1 stimulates microtubule depolymerization and interferes with taxane binding to b-tubulin subunits (26).…”

Effects of Monoclonal Antibodies against Human Stathmin Combined with Paclitaxel on Proliferation of the QG-56 Human Lung Carcinoma Cell Line

“…Studies confirmed that stathmin overexpression is associated with the sensitivity of lung cancer cells to vindesine, which could be used as a marker of vinca alkaloids-sensitive in lung cancer patients. The combination of paclitaxel and anti-stathmin provides an effective, low toxicity treatment, which is much safer than the combination of multiple chemotherapy drugs that may cause the toxicity accumulation (Alli et al, 2002;Balachandran et al, 2003).…”