Thyroid hormone depletion inhibits astrocytoma proliferation via a p53-independent induction of p21 (WAF1/CIP1).
BACKGROUND
Clinical hypothyroidism has been associated with prolonged survival in several types of malignancies, but the mechanism of this effect is unknown.


METHODS
In vitro studies of thyroid hormone depletion (via culture in medium containing 5% thyroid hormone-depleted fetal bovine serum (FBS)) were carried out using a human glioblastoma cell line (WITG3) which expresses a mutant, non-functional p53.


RESULTS
Thyroid hormone depletion inhibited WITG3 proliferation compared to control medium containing 5% euthyroid FBS. There was no evidence of apoptosis and viability was not compromised. Cell cycle analysis by flow cytometry indicated that thyroid hormone depletion accumulated WITG3 cells in G1, with fewer cells progressing into S than in euthyroid medium. By immunoblotting, p21 (WAF1/CIP1) was only slightly detectable in lysates from WITG3 cells grown in control euthyroid medium; however, in thyroid hormone-depleted FBS, a marked induction of p2 1 occurred which could be reversed by exogenous thyroid hormone


CONCLUSIONS
These data indicate that thyroid hormone depletion may cause a G, arrest in astrocytoma mediated by a p53-independent induction of p21 (WAF1/CIP1). Results suggest a mechanism which may explain the effect of hypothyroidism on suppression of tumor cell growth.
Toms
S A
SA
Department of Neurological Surgery, Cleveland Clinic Foundation, OH 44195, USA.
Hercbergs
A
A
Liu
J
J
Kondo
S
S
Barnett
G H
GH
Casey
G
G
Barna
B P
BP
D017209:Apoptosis; D001254:Astrocytoma / Q000473:pathology*; D002453:Cell Cycle; D002455:Cell Division; D002470:Cell Survival; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism*; D053938:DNA Fragmentation; D006801:Humans; D013963:Thyroid Hormones / Q000172:deficiency / Q000502:physiology*; D014407:Tumor Cells, Cultured
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D013963:Thyroid Hormones