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Mol Cancer Res. 2009 Oct;7(10):1645-54. doi: 10.1158/1541-7786.MCR-09-0117. Epub 2009 Oct 13.

Mutant p53 (G199V) gains antiapoptotic function through signal transducer and activator of transcription 3 in anaplastic thyroid cancer cells.

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1
Department of Anatomy and Cell Biology, Dong-A University College of Medicine and Medical Science Research Center, Busan, South Korea.

Abstract

In the present study, we identified a missense mutation (G199V) in KAT-18 cell line established from primary cultures of anaplastic thyroid cancer (ATC). Notably, knockdown of this mutant (mt) p53 reduced cell viability and exerted antitumor activity equivalent to high doses of several chemotherapeutic agents. We showed that p53 knockdown had an antitumor effect via the induction of apoptosis. We further examined the underlying mechanism by which mt p53 (G199V) gains antiapoptotic function in KAT-18 cells. Microarray analysis revealed that p53 knockdown modified the expression of numerous apoptosis-related genes. Importantly, p53 knockdown led to downregulation of signal transducer and activator of transcription-3 (STAT3) gene expression. We further observed that p53 knockdown induced the downregulation of STAT3 protein. We also observed that a STAT3 inhibitor augmented the reduction of cell viability induced by p53 knockdown, whereas interleukin-6 treatment alleviated this effect. In addition, overexpression of STAT3 protected ATC cells against cell death induced by p53 knockdown. Taken together, these data show that mt p53 (G199V) gains antiapoptotic function mediated by STAT3 in ATC cells. Inhibition of the function of mt p53 (G199V) could be a novel and useful therapeutic strategy for decreasing the extent and severity of toxicity due to chemotherapeutic agents.

PMID:
19825993
DOI:
10.1158/1541-7786.MCR-09-0117
[Indexed for MEDLINE]
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