Three-dimensional collagen type I matrix up-regulates nuclear isoforms of the microtubule associated protein tau implicated in resistance to paclitaxel therapy in ovarian carcinoma

• Published in: International journal of molecular sciences Vol. 16; no. 2; pp. 3419 - 3433
• Main Authors: Gurler, Hilal, Yu, Yi, Choi, Jacqueline, Kajdacsy-Balla, Andre A, Barbolina, Maria V
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 04.02.2015; MDPI
• Subjects: Antineoplastic Agents, Phytogenic - pharmacology; Antineoplastic Agents, Phytogenic - therapeutic use; Cancer therapies; Carcinoma, Ovarian Epithelial; Cell Culture Techniques; Collagen; Collagen Type I - metabolism; Drug Resistance, Neoplasm - genetics; Female; Gene Silencing; Humans; Immunohistochemistry; Matrix; microtubule associated protein tau; Neoplasm Metastasis; Neoplasm Staging; Neoplasms, Glandular and Epithelial - drug therapy; Neoplasms, Glandular and Epithelial - genetics; Neoplasms, Glandular and Epithelial - metabolism; Neoplasms, Glandular and Epithelial - pathology; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; paclitaxel; Paclitaxel - pharmacology; Paclitaxel - therapeutic use; Protein Isoforms; Proteins; RNA Interference; RNA, Small Interfering - genetics; serous epithelial ovarian carcinoma; tau Proteins - genetics; tau Proteins - metabolism; three-dimensional collagen matrix
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms16023419

Epithelial ovarian carcinoma is the deadliest gynecologic malignancy. One reason underlying treatment failure is resistance to paclitaxel. Expression of the microtubule associated protein tau has recently been proposed as a predictor of response to paclitaxel in ovarian carcinoma patients. Expression of tau was probed using immunohistochemistry in 312 specimens of primary, and 40 specimens of metastatic, ovarian carcinoma. Serous epithelial ovarian carcinoma cell line models were used to determine the expression of tau by Western blot and immunofluorescence staining. Subcellular fractionation and Western blot were employed to examine nuclear and cytoplasmic localization of tau. Gene silencing and clonogenic assays were used to evaluate paclitaxel response. Tau was expressed in 44% of all tested cases. Among the primary serous epithelial ovarian carcinoma cases, 46% were tau-positive. Among the metastatic serous epithelial ovarian carcinomas, 63% were tau-positive. Cell culture experiments demonstrated that tau was expressed in multiple isoforms. Three-dimensional collagen I matrix culture conditions resulted in up-regulation of tau protein. Silencing of tau with specific siRNAs in a combination with three-dimensional culture conditions led to a significant decrease of the clonogenic ability of cells treated with paclitaxel. The data suggest that reduction of tau expression may sensitize ovarian carcinoma to the paclitaxel treatment.