Reverse transcriptase inhibitors down-regulate cell proliferation in vitro and in vivo and restore thyrotropin signaling and iodine uptake in human thyroid anaplastic carcinoma.
BACKGROUND
Two classes of repeated genomic elements, retrotransposons and endogenous retroviruses, encode for endogenous nontelomeric reverse transcriptase (RT), a gene that is down-regulated in differentiated cells but is highly expressed in embryonic and transformed tissues. Two nonnucleosidic RT inhibitors, efavirenz and nevirapine, currently used in HIV treatment, reversibly down-regulate tumor growth and induce differentiation in several human tumor cell models.


OBJECTIVE
Aggressive biological behavior and loss of specific thyroid cell functions, such as thyroglobulin, thyroid peroxidase, TSH receptor, Na/I symporter expression, and iodine uptake are features of anaplastic thyroid cancer. Thus, we evaluated the use of RT inhibitors as a potentially differentiating and molecular-targeted treatment of this neoplasm.


RESULTS
Our findings showed that nevirapine and efavirenz reversibly inhibit cell proliferation without triggering cell death in the undifferentiated thyroid carcinoma ARO and FRO cells, which exhibited high levels of endogenous RT activity. Inhibition of cell growth was correlated with accumulation of cells in the G0/G1 phase of the cell cycle, with a concomitant decrease in the S phase. Moreover, treated cells demonstrated a differentiated phenotype and a significant reprogramming of gene expression characterized by up-regulation of the TSH receptor, thyroglobulin, thyroid peroxidase, and Na/I symporter genes. Interestingly, RT inhibition reestablished the ability to uptake iodine in response to TSH either in vitro or in vivo and reversibly down-regulated tumor growth in mice xenografts of ARO cells.


CONCLUSIONS
These findings support the need for clinical trials to clarify whether RT inhibitors may restore the sensitivity to radiometabolic therapy in anaplastic thyroid tumors.
Landriscina
Matteo
M
Dipartimento di Scienze Mediche e del Lavoro, Università degli Studi di Foggia, Viale Pinto, 1-71100 Foggia, Italy. m.landriscina@unifg.it
Fabiano
Annarita
A
Altamura
Settimia
S
Bagalà
Cinzia
C
Piscazzi
Annamaria
A
Cassano
Alessandra
A
Spadafora
Corrado
C
Giorgino
Francesco
F
Barone
Carlo
C
Cignarelli
Mauro
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D015151:Immunoblotting; D007455:Iodine / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009336:Necrosis; D009368:Neoplasm Transplantation; D012194:RNA-Directed DNA Polymerase / Q000378:metabolism; D011989:Receptors, Thyrotropin / Q000096:biosynthesis; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D013964:Thyroid Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology*; D013972:Thyrotropin / Q000502:physiology*; D014183:Transplantation, Heterologous
D011989:Receptors, Thyrotropin; D018894:Reverse Transcriptase Inhibitors; D013972:Thyrotropin; D007455:Iodine; D012194:RNA-Directed DNA Polymerase