Targeting STAT3 by HO3867 induces apoptosis in ovarian clear cell carcinoma.
Targeting STAT3 by HO3867 induces apoptosis in ovarian clear cell carcinoma.
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DOI：
10.1002/ijc.30847
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发表时间：
2017-11-01
影响因子：
6.4
通讯作者：
Selvendiran K
中科院分区：
文献类型：
--
作者：
Bixel K;Saini U;Kumar Bid H;Fowler J;Riley M;Wanner R;Deepa Priya Dorayappan K;Rajendran S;Konishi I;Matsumura N;Cohn DE;Selvendiran K
晚期卵巢透明细胞癌（OCCC）预后极差，这在很大程度上是由于对标准铂类和紫杉烷类化疗的极高耐药率。STAT 3的表达和激活已被证明在各种人类癌症中调节肿瘤进展，尽管在OCCC中尚未得到充分研究。我们实验室的初步工作已经证明了STAT 3（pSTAT 3 Tyr 705或pSTAT 3727）在OCCC细胞系以及人OCCC肿瘤组织样品中的组成性激活。值得注意的是，pSTAT 3在没有其他形式的活化STAT（pSTAT 1，2，6）的情况下表达。因此，这项工作计划使用已知的OCCC细胞系来研究STAT 3的作用，并检查新型抗癌化合物HO-3867（其是STAT 3的抑制剂）的功效。结果表明，用HO-3867处理降低了pSTAT 3 Tyr 705以及pSTAT 3 Ser 727的表达，而总STAT 3保持恒定。STAT 3过表达增加了体外OVTOKO细胞的迁移能力，并导致体内注射时肿瘤大小增加。HO-3867对细胞增殖和细胞存活的抑制作用伴随着处理后24小时内细胞凋亡的增加。用HO-3867处理导致Bcl-2减少和半胱天冬酶3、半胱天冬酶7和PARP的裂解增加，证实了用HO-3867处理后诱导细胞凋亡。此外，HO-3867在5和10μM浓度下均显著抑制HUVEC细胞毛细血管样结构的形成和侵袭。STAT 3的表达在OCCC的体内外扩散中起重要作用。因此，我们可以利用STAT 3通路进行靶向药物治疗。在OCCC细胞系中使用HO-3867抑制pSTAT 3似乎是一种有希望的治疗方法。鉴于OCCC对标准化疗方案的反应较差，这一点至关重要。
Advanced ovarian clear cell carcinoma (OCCC) carries a very poor prognosis in large part secondary to the extremely high rate of resistance to standard platinum and taxane chemotherapy. STAT3 expression and activation has been shown to regulate tumor progression in various human cancers, though has not been well studied in OCCC. Preliminary work in our lab has demonstrated constitutive activation of STAT3 (pSTAT3Tyr705 or pSTAT3727) in OCCC cell lines as well as human OCCC tumor tissue samples. Significantly, pSTAT3 is expressed in the absence of other forms of activated STAT (pSTAT1, 2, 6). Therefore, this work was planned to investigate the role of STAT3 and examine the efficacy of a novel anti-cancer compound -HO-3867, which is an inhibitor of STAT3, using known OCCC cell lines. Results demonstrate that treatment with HO-3867 decreased expression of pSTAT3 Tyr705 as well pSTAT3 Ser727, while total STAT3 remained constant. STAT3 overexpression increased the migration capability in OVTOKO cells in vitro and led to an increased tumor size when injected in vivo. The inhibitory effect of HO-3867 on cell proliferation and cell survival was accompanied by increased apoptosis, within 24 h post treatment. Treatment with HO-3867 resulted in a decrease in Bcl-2 and increase of cleavage of caspase 3, caspase 7, and PARP, confirming induction of apoptosis after treatment with HO-3867. In addition, HO-3867 significantly inhibited formation of HUVEC cells capillary-like structures and invasion at both 5 and 10μM concentrations. STAT3 expression plays an important role in the spread of OCCC in vitro as well as in vivo. Thus, we can exploit the STAT3 pathway for targeted drug therapy. Inhibition of pSTAT3 using HO-3867in OCCC cell lines appears to be a promising therapy. This is of utmost importance given the poor response of OCCC to standard chemotherapy regimens.
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影响因子：
5.7
作者：
Selvendiran K;Tong L;Bratasz A;Kuppusamy ML;Ahmed S;Ravi Y;Trigg NJ;Rivera BK;Kálai T;Hideg K;Kuppusamy P
通讯作者：
Kuppusamy P
影响因子：
5.7
作者：
Hisamatsu T;Mabuchi S;Matsumoto Y;Kawano M;Sasano T;Takahashi R;Sawada K;Ito K;Kurachi H;Schilder RJ;Testa JR;Kimura T
通讯作者：
Kimura T
影响因子：
8
作者：
Saini U;Naidu S;ElNaggar AC;Bid HK;Wallbillich JJ;Bixel K;Bolyard C;Suarez AA;Kaur B;Kuppusamy P;Hays J;Goodfellow PJ;Cohn DE;Selvendiran K
通讯作者：
Selvendiran K
影响因子：
6.2
作者：
Rosen, Daniel G.;Mercado-Uribe, Imelda;Liu, Jinsong
通讯作者：
Liu, Jinsong
影响因子：
7.4
作者：
Selvendiran, Karuppaiyah;Ahmed, Shabnam;Dayton, Alex;Kuppusamy, M. Lakshmi;Tazi, Mia;Bratasz, Anna;Tong, Liyue;Rivera, Brian K.;Kalai, Tamas;Hideg, Kalman;Kuppusamy, Periannan
通讯作者：
Kuppusamy, Periannan