Spectrin αII and βII tetramers contribute to platinum anticancer drug resistance in ovarian serous adenocarcinoma

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 alpha II and beta II by peptide mass mapping analysis. Western blot analysis detected greater expression of spectrin alpha II and beta II in NOS2CR2 than in wild-type cells (NOS2). The same result was obtained for spectrin beta II expression by immunohistochemical staining. To determine whether spectrin alpha II and beta II 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 beta II expression than untreated specimens. Fifty-two tumor specimens from 46 patients with ovarian serous adenocarcinoma were immunohistochemically stained for spectrin beta II 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 alpha II and beta II contributed to drug resistance by anchoring the GS-Pt complex to the cell membrane, arresting cisplatin activity. Thus spectrin beta II may be a useful predictor of platinum sensitivity in ovarian serous adenocarcinoma.