The MEK1/2 Pathway as a Therapeutic Target in High-Grade Serous Ovarian Carcinoma.
The MEK1/2 Pathway as a Therapeutic Target in High-Grade Serous Ovarian Carcinoma.
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MEK1/2通路作为高级别浆液性卵巢癌的治疗靶点
DOI：
10.3390/cancers13061369
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发表时间：
2021-03-18
期刊：
影响因子：
5.2
通讯作者：
Chefetz I
中科院分区：
文献类型：
--
作者：
Chesnokov MS;Khan I;Park Y;Ezell J;Mehta G;Yousif A;Hong LJ;Buckanovich RJ;Takahashi A;Chefetz I
高级别浆液性卵巢癌(HGSOC)由于复发率高、获得性耐药，患者预后较差。控制细胞增殖和存活的MEK1/2-ERK1/2信号通路在大多数HGSOC病例中是活跃的，但其功能影响尚不清楚。我们认为，用特异性抑制剂曲美替尼抑制MEK1/2可能对HGSOC细胞具有抗癌作用。在这里，我们证明了曲美替尼处理HGSOC细胞确实显著地抑制了细胞增殖和肿瘤生长，并且具有高MEK1/2活性的顺铂耐药细胞对曲美替尼特别敏感。然而，我们也发现，曲美替尼处理HGSOC细胞没有细胞毒性作用，并促进了肿瘤干细胞样特性。因此，我们建议将MEK1/2抑制剂与其他针对肿瘤干细胞的治疗策略一起使用，如乙醛脱氢酶1的抑制，这可能会显示出很强的协同作用。高级别浆液性卵巢癌(HGSOC)因其高复发率和获得性化疗耐药而成为妇科癌症中死亡率最高的肿瘤。RAS/MEK/ERK通路激活与细胞增殖和耐药有关，但MEK1/2-ERK1/2通路在HGSOC中的作用研究较少。我们用免疫组织化学、免疫印迹和RT-qPCR方法研究了临床HGSOC标本和卵巢癌细胞系中MEK1/2通路的活性。体外培养HGSOC细胞，观察曲美替尼对MEK1/2的即刻和持久抑制作用。采用小鼠移植瘤模型，观察曲美替尼对肿瘤生长的影响。MEK1/2通路在HGSOC中被过度激活，并被顺铂进一步刺激。曲美替尼治疗导致细胞周期停滞于G1/0期，并降低体内肿瘤生长速度，但不会诱导细胞死亡或减少CD133+干细胞的比例，相反，会增加干细胞相关基因的表达。短暂的曲美替尼治疗导致高醛脱氢酶(ALDH)1活性的细胞亚群长期增加，这些细胞可以在非贴壁条件下存活和生长。我们得出结论，抑制MEK1/2可能是抑制卵巢癌生长作为维持治疗的一种有前途的方法。抑制MEK1/2后促进干细胞样特性提示了一种可能的耐药机制，因此应考虑与CSC靶向药物联合使用。
High-grade serous ovarian carcinoma (HGSOC) has poor prognosis for patients due to its high rate of recurrence and acquired resistance to therapy. MEK1/2-ERK1/2 signaling pathway that controls cell proliferation and survival is active in the majority of HGSOC cases, but its functional impact is unclear. We suggest that inhibition of MEK1/2 with specific inhibitor trametinib may exert anti-cancer effects upon HGSOC cells. Here we demonstrate that trametinib treatment of HGSOC cells indeed prominently inhibits cell proliferation and tumor growth, and that cisplatin-resistant cells displaying high MEK1/2 activity are particularly sensitive to trametinib. However, we also discovered that trametinib treatment of HGSOC cells has no cytotoxic effects and promotes cancer stem-like characteristics. We therefore suggest to use MEK1/2 inhibitors with other treatment strategies targeting cancer stem-like cells, like aldehyde dehydrogenase 1 inhibition that might show together strong synergy. High-grade serous ovarian carcinoma (HGSOC) is the deadliest of gynecological cancers due to its high recurrence rate and acquired chemoresistance. RAS/MEK/ERK pathway activation is linked to cell proliferation and therapeutic resistance, but the role of MEK1/2-ERK1/2 pathway in HGSOC is poorly investigated. We evaluated MEK1/2 pathway activity in clinical HGSOC samples and ovarian cancer cell lines using immunohistochemistry, immunoblotting, and RT-qPCR. HGSOC cell lines were used to assess immediate and lasting effects of MEK1/2 inhibition with trametinib in vitro. Trametinib effect on tumor growth in vivo was investigated using mouse xenografts. MEK1/2 pathway is hyperactivated in HGSOC and is further stimulated by cisplatin treatment. Trametinib treatment causes cell cycle arrest in G1/0-phase and reduces tumor growth rate in vivo but does not induce cell death or reduce fraction of CD133+ stem-like cells, while increasing expression of stemness-associated genes instead. Transient trametinib treatment causes long-term increase in a subpopulation of cells with high aldehyde dehydrogenase (ALDH)1 activity that can survive and grow in non-adherent conditions. We conclude that MEK1/2 inhibition may be a promising approach to suppress ovarian cancer growth as a maintenance therapy. Promotion of stem-like properties upon MEK1/2 inhibition suggests a possible mechanism of resistance, so a combination with CSC-targeting drugs should be considered.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
8
作者：
Cooke, S. L.;Ng, C. K. Y.;Melnyk, N.;Garcia, M. J.;Hardcastle, T.;Temple, J.;Langdon, S.;Huntsman, D.;Brenton, J. D.
通讯作者：
Brenton, J. D.
影响因子：
11.2
作者：
Hoeflich, Klaus P.;Merchant, Mark;Belvin, Marcia
通讯作者：
Belvin, Marcia
DOI：
10.1016/j.bbrc.2013.06.114
发表时间：
2013-08-09
影响因子：
3.1
作者：
Ahn, Hee-Jin;Kim, Gwangil;Park, Kyung-Soon
通讯作者：
Park, Kyung-Soon
影响因子：
4.3
作者：
Chefetz, Ilana;Alvero, Ayesha B.;Mor, Gil
通讯作者：
Mor, Gil