Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Mutant p53 (G199V) gains antiapoptotic function through signal transducer and activator of transcription 3 in anaplastic thyroid cancer cells. 1982 93

Background: Metformin has antitumoral actions in human cancers, including the thyroid, while its effects on metastatic lesions are unclear. Patients with bone metastasis (BM) from thyroid cancers have poor survival. Because metformin inhibits the activation of osteoclasts, which has essential roles in BM, the aim of this study was to investigate the therapeutic effects of metformin on thyroid cancer BM and osteoclast activation in the bone microenvironment. Methods: The anaplastic thyroid cancer (ATC) cell lines FRO and SW1736 were used to test the antitumoral effect of metformin in vitro and in vivo. A murine model of BM was established by intratibial injection of cancer cells. To mimic the BM microenvironment, osteoblasts were treated with conditioned media from the FRO (FRO-CM) and SW1736 (SW1736-CM) cells. Thyroid cancer patients with or without BM were recruited, and the serum receptor activator of nuclear factor kappa-B ligand (RANKL) levels was measured. Results: Metformin treatment significantly reduced the viabilities of the FRO and SW1736 cells in vitro and the tumor growth of SW1736 in vivo. In the murine model of BM, metformin delayed tumor growth in the bone and decreased the numbers of tartrate-resistant acid phosphatase-positive osteoclasts on the bone surface with reduced RANKL in the bone marrow. Furthermore, FRO- or SW1736-CM significantly increased the osteoblastic RANKL productions and activated osteoclast differentiation in whole marrow cultures, which were blocked by metformin treatment. Among 67 thyroid cancer patients, the serum RANKL levels were significantly increased in BM patients compared with patients with lung-only metastasis or no distant metastasis. In addition, the interleukin-6 superfamily in the FRO- or SW1736-CM stimulated STAT3 phosphorylation, which was inhibited by gp130 blocking. Metformin treatment decreased the FRO- or SW1736-CM-induced STAT3 phosphorylation by AMPK phosphorylation. Metformin also inhibited the FRO- or SW1736-CM-induced osteoclastic differentiation of bone marrow-derived monocyte/macrophage by RANK/c-Fos/NFATC1 signaling. Conclusions: In the microenvironment of BM, metformin effectively reduced ATC tumor growth by inhibiting cancer cell viability, blocking cancer cell-induced osteoblastic RANKL production, which further activated osteoclastogenesis, and directly reduced osteoclast differentiation. These multifactorial actions of metformin suggest that it has potential therapeutic effects in thyroid cancer BM.
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PMID:Metformin Reduces Thyroid Cancer Tumor Growth in the Metastatic Niche of Bone by Inhibiting Osteoblastic RANKL Productions. 3279 89