title: Spectrin αII and βII tetramers contribute to platinum anticancer drug resistance in ovarian serous adenocarcinoma.
abstract: To overcome drug resistance in ovarian carcinoma, novel resistance mechanisms must be elucidated for clinical application. We purified 2 proteins in the 300 kDa range from cisplatin-resistant cells (NOS2CR2) by affinity chromatography with cisplatin-exposed Glutathione Sepharose 4B. The purified proteins were identified as spectrin αII and βII by peptide mass mapping analysis. Western blot analysis detected greater expression of spectrin αII and βII in NOS2CR2 than in wild-type cells (NOS2). The same result was obtained for spectrin βII expression by immunohistochemical staining. To determine whether spectrin αII and βII contribute to resistance, a drug sensitivity test was performed on SKOV3 ovarian cancer cells transfected with small interfering RNA. Sensitivity to platinum drugs was increased in the expression reduced cells. In a clinical study of five ovarian serous adenocarcinoma cases, tumor specimens taken after treatment with carboplatin stained more strongly for spectrin βII expression than untreated specimens. Fifty-two tumor specimens from 46 patients with ovarian serous adenocarcinoma were immunohistochemically stained for spectrin βII and scored. Tumors previously treated by chemotherapy scored higher than those not treated. Of 27 cases with detectable residual tumors at the time of surgery, cases scoring 4-6 had shorter progression-free survival periods after platinum-based chemotherapy than cases scoring 0-3 (p = 0.012). The cytoskeleton proteins Spectrin αII and βII contributed to drug resistance by anchoring the GS-Pt complex to the cell membrane, arresting cisplatin activity. Thus spectrin βII may be a useful predictor of platinum sensitivity in ovarian serous adenocarcinoma.
authors.affiliation: Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan. osamumaeda@med.nagoya-u.ac.jp
authors.forename: Osamu
authors.initials: O
authors.lastname: Maeda
authors.forename: Kiyosumi
authors.initials: K
authors.lastname: Shibata
authors.forename: Satoyo
authors.initials: S
authors.lastname: Hosono
authors.forename: Sawako
authors.initials: S
authors.lastname: Fujiwara
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kajiyama
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Ino
authors.forename: Akihiro
authors.initials: A
authors.lastname: Nawa
authors.forename: Koji
authors.initials: K
authors.lastname: Tamakoshi
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Kikkawa
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D002945:Cisplatin / Q000008:administration & dosage; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D055503:Protein Multimerization; D034741:RNA, Small Interfering / Q000235:genetics; D013049:Spectrin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D034741:RNA, Small Interfering; C452439:SPTBN1 protein, human; D013049:Spectrin; D016190:Carboplatin; D002945:Cisplatin