1. Detailed molecular fingerprinting of four new anaplastic thyroid carcinoma cell lines and their use for verification of RhoB as a molecular therapeutic target.
- Author
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Marlow LA, D'Innocenzi J, Zhang Y, Rohl SD, Cooper SJ, Sebo T, Grant C, McIver B, Kasperbauer JL, Wadsworth JT, Casler JD, Kennedy PW, Highsmith WE, Clark O, Milosevic D, Netzel B, Cradic K, Arora S, Beaudry C, Grebe SK, Silverberg ML, Azorsa DO, Smallridge RC, and Copland JA
- Subjects
- Antineoplastic Agents pharmacology, Apoptosis drug effects, Blotting, Western, Cell Division drug effects, Cell Line, Tumor, DNA Fingerprinting, DNA, Neoplasm genetics, DNA, Neoplasm isolation & purification, Dimethyl Sulfoxide pharmacology, Flow Cytometry, Genetic Markers, Humans, Thyroid Carcinoma, Anaplastic, Thyroid Neoplasms drug therapy, Thyroid Neoplasms genetics, Thyroid Neoplasms pathology, Transfection, rhoB GTP-Binding Protein drug effects, rhoB GTP-Binding Protein genetics, Antineoplastic Agents therapeutic use, Microsatellite Repeats genetics, Mutation, rhoB GTP-Binding Protein metabolism
- Abstract
Context: Anaplastic thyroid carcinoma (ATC) is a highly aggressive carcinoma in need of therapeutic options. One critical component of drug discovery is the availability of well-characterized cell lines for identification of molecular mechanisms related to tumor biology and drug responsiveness. Up to 42% of human thyroid cancer cell lines are redundant or not of correct tissue origin, and a comprehensive analysis is currently nonexistent. Mechanistically, RhoB has been identified as a novel molecular target for ATC therapy., Objective: The aim was to develop four ATC cell lines detailing genetic, molecular, and phenotypic characteristics and to test five classes of drugs on the cell lines to determine whether they inhibited cell proliferation in a RhoB-dependent fashion., Design: Four cell lines were derived from ATC tumors. Short tandem DNA repeat and mutational status of the originating tumors and cell lines were performed along with molecular and phenotypic characterizations. Compounds were tested for growth inhibition and ability to up-regulate RhoB., Results: Cell line authenticity was confirmed by DNA short tandem repeat analysis. Each proved unique regarding expression of thyroid markers, oncogene status, amplified and deleted genes, and proliferative growth rates. FTI-277, GGTI-286, lovastatin, romidepsin, and UCN-01 up-regulated RhoB and inhibited cell proliferation in a dose-responsive fashion with only romidepsin and FTI-277 being RhoB dependent., Conclusions: Molecular descriptions of thyroid lines were matched to the originating tumors, setting a new standard for cell line characterization. Furthermore, suppressed RhoB is implicated as a molecular target for therapy against ATC because five classes of drugs up-regulate RhoB and inhibit growth dose-responsively.
- Published
- 2010
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