The STAT3 inhibitor NSC 74859 is effective in hepatocellular cancers with disrupted TGF-beta signaling.
The STAT3 inhibitor NSC 74859 is effective in hepatocellular cancers with disrupted TGF-beta signaling.
复制标题
DOI：
10.1038/onc.2008.448
复制
发表时间：
2009-02-19
期刊：
影响因子：
8
通讯作者：
He, A. R.
中科院分区：
文献类型：
--
作者：
Lin, L.;Amin, R.;Gallicano, G. I.;Glasgow, E.;Jogunoori, W.;Jessup, J. M.;Zasloff, M.;Marshall, J. L.;Shetty, K.;Johnson, L.;Mishra, L.;He, A. R.
肝细胞癌是全球癌症死亡的第三大原因，对晚期疾病几乎没有有效的治疗选择。至少40%的肝细胞癌是克隆性的，可能源于STAT3+、NANOG+和OCT3/4+肝干细胞转化，以及转化生长因子-β(TGFR-β)信号失活。在这里，我们报告了在人肝细胞癌组织中信号转导和转录激活因子3(STAT3)和酪氨酸磷酸化的STAT3(分别为P<；0.0030和P<；0.0455)比在人类正常肝脏中显著增加。此外，在对转化生长因子-β失去反应的肝癌细胞中，STAT3特异性抑制剂NSC 74859显著抑制生长。相反，CD133+状态不影响对STAT3抑制的反应：CD133+Huh-7细胞和CD133−Huh-7细胞对NSC 74859处理和STAT3抑制都同样敏感，IC50值为100μM。因此，β-β/Beta2 Spectrin(TGF2SP)通路可能比CD133更能反映一种功能更强的“干/祖”状态。此外，NSC 74859对裸鼠移植瘤HuH-7的治疗明显抑制肿瘤生长，有效剂量仅为5 mg/kg。此外，神经干细胞74859在体内抑制肝癌细胞中STAT3的酪氨酸磷酸化。我们认为，通过阻断转化生长因子-β/β-2SP途径抑制肝癌细胞中IL-6/STAT3的表达是治疗肝癌的有效途径。因此，作为肝细胞癌干细胞更新和增殖的主要信号通路，IL6/STAT3可以为治疗特定的肝癌提供一种新的途径。
Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide, with few effective therapeutic options for advanced disease. At least 40% of HCCs are clonal, potentially arising from STAT3 +, NANOG + and OCT3/4 + liver progenitor/stem cell transformation, along with inactivation of transforming growth factor-beta (TGF-β) signaling. Here we report significantly greater signal transducer and activator of transcription 3 (STAT3) and tyrosine phosphorylated STAT3 in human HCC tissues (P<0.0030 and P<0.0455, respectively) than in human normal liver. Further, in HCC cells with loss of response to TGF-β, NSC 74859, a STAT3-specific inhibitor, markedly suppresses growth. In contrast, CD133+ status did not affect the response to STAT3 inhibition: both CD133+ Huh-7 cells and CD133− Huh-7 cells are equally sensitive to NSC 74859 treatment and STAT3 inhibition, with an IC50 of 100 μM. Thus, the TGF-β/beta2 spectrin (β2SP) pathway may reflect a more functional ‘stem/progenitor’ state than CD133. Furthermore, NSC 74859 treatment of Huh-7 xenografts in nude mice significantly retarded tumor growth, with an effective dose of only 5 mg/kg. Moreover, NSC 74859 inhibited tyrosine phosphorylation of STAT3 in HCC cells in vivo. We conclude that inhibiting interleukin 6 (IL6)/STAT3 in HCCs with inactivation of the TGF-β/β2SP pathway is an effective approach in management of HCCs. Thus, IL6/STAT3, a major signaling pathway in HCC stem cell renewal and proliferation, can provide a novel approach to the treatment of specific HCCs.
登录
查看更多内容
DOI：
10.1152/ajpgi.00456.2005
发表时间：
2006-05-01
影响因子：
4.5
作者：
Sicklick, JK;Li, YX;Diehl, AM
通讯作者：
Diehl, AM
影响因子：
4.7
作者：
Sicklick, JK;Li, YX;Diehl, AM
通讯作者：
Diehl, AM
影响因子：
11.2
作者：
Frank, NY;Margaryan, A;Frank, MH
通讯作者：
Frank, MH
影响因子：
4.8
作者：
Lim, CP;Cao, XM
通讯作者：
Cao, XM
影响因子：
8
作者：
Kanzler, S;Meyer, E;Blessing, M
通讯作者：
Blessing, M