TY - JOUR
T1 - Detailed molecular fingerprinting of four new anaplastic thyroid carcinoma cell lines and their use for verification of RhoB as a molecular therapeutic target
AU - Marlow, Laura A.
AU - D'Innocenzi, Jaclyn
AU - Zhang, Yilin
AU - Rohl, Stephen D.
AU - Cooper, Simon J.
AU - Sebo, Thomas
AU - Grant, Clive
AU - McIver, Bryan
AU - Kasperbauer, Jan L.
AU - Wadsworth, J. Trad
AU - Casler, John D.
AU - Kennedy, Pamela W.
AU - Highsmith, W. Edward
AU - Clark, Orlo
AU - Milosevic, Dragana
AU - Netzel, Brian
AU - Cradic, Kendall
AU - Arora, Shilpi
AU - Beaudry, Christian
AU - Grebe, Stefan K.
AU - Silverberg, Marc L.
AU - Azorsa, David O.
AU - Smallridge, Robert C.
AU - Copland, John A.
N1 - Funding Information:
Disclosure Summary: R.C.S. (Principal Investigator) received grant support for a clinical trial with Daiichi Sankyo Inc. (1/11/2008—12/31/2009) . J.A.C. (Principal Investigator) received grant support from Daiichi Sankyo Inc. (6/1/2009—5/31/2010) . The remaining authors have nothing to disclose.
Funding Information:
This work was funded in part from National Institutes of Health (NIH) Grant P30CA15083 (Cancer Center Support Grant, to R.C.S.), the Mayo Clinic Research Committee (to R.C.S.), Bankhead-Coley Cancer Research Program, Florida Department of Health (to J.A.C. and R.C.S.), NIH Grant R01CA136665 (to J.A.C. and R.C.S.), and a grant for rare cancers from Dr. Ellis and Dona Brunton (to J.A.C.).
PY - 2010/12
Y1 - 2010/12
N2 - 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.
AB - 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.
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U2 - 10.1210/jc.2010-1421
DO - 10.1210/jc.2010-1421
M3 - Article
C2 - 20810568
AN - SCOPUS:78650039981
SN - 0021-972X
VL - 95
SP - 5338
EP - 5347
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 12
ER -