Class III beta-tubulin overexpression is a prominent mechanism of paclitaxel resistance in ovarian cancer patients.
The vast majority of women with advanced ovarian cancer will ultimately relapse and develop a drug-resistant disease with an overall 5-year survival of <50%. Unfortunately, the mechanisms of drug resistance actually operating in patients are still unknown. To address this issue, in 41 patients affected by advanced ovarian cancer the three main mechanisms of paclitaxel resistance were investigated: overexpression of MDR-1 gene, point mutations at prominently expressed alpha-tubulin and beta-tubulin genes and selective alterations in the expression of beta-tubulin isotypes. MDR-1 and the beta-tubulin isotypes expression were evaluated by semiquantitative and real-time PCR. On the same specimens, quantitative immunohistochemistry was also done in the tumor area. No statistically significant changes of MDR-1 expression were noticed between the sensitive and resistant patients either at the mRNA or protein level. The tubulin mutations for the ubiquitous alpha-tubulin and beta-tubulin genes were evaluated by automated DNA sequencing, and in all patients, no mutations were detected in both resistant and sensitive cases. With regard to the expression of tubulin isoforms, a statistically significant up-regulation of class III beta-tubulin was found in the resistant subset. It is worth noting that this statistically significant increase of the expression of class III beta-tubulin was detectable at the mRNA and protein level. By a direct comparison of the three main known mechanisms of paclitaxel resistance, this study indicates that overexpression of class III beta-tubulin is the most prominent mechanism of paclitaxel resistance in ovarian cancer.
Mozzetti
Simona
S
Laboratory of Antineoplastic Pharmacology, Università Cattolica Sacro Cuore, Rome, Italy.
Ferlini
Cristiano
C
Concolino
Paola
P
Filippetti
Flavia
F
Raspaglio
Giuseppina
G
Prislei
Silvia
S
Gallo
Daniela
D
Martinelli
Enrica
E
Ranelletti
Franco Oreste
FO
Ferrandina
Gabriella
G
Scambia
Giovanni
G
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis; D000328:Adult; D000368:Aged; D001483:Base Sequence; D015331:Cohort Studies; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D017239:Paclitaxel / Q000627:therapeutic use*; D017354:Point Mutation; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D013997:Time Factors; D016896:Treatment Outcome; D014404:Tubulin / Q000096:biosynthesis* / Q000737:chemistry; D015854:Up-Regulation
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D020033:Protein Isoforms; D012333:RNA, Messenger; D014404:Tubulin; D017239:Paclitaxel