Panobinostat Enhances Growth Suppressive Effects of Progestin on Endometrial Carcinoma by Increasing Progesterone Receptor and Mitogen-Inducible Gene-6
Panobinostat Enhances Growth Suppressive Effects of Progestin on Endometrial Carcinoma by Increasing Progesterone Receptor and Mitogen-Inducible Gene-6
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DOI：
10.1007/s12672-017-0295-4
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发表时间：
2017-08-01
影响因子：
3
通讯作者：
Shiozawa, Tanri
中科院分区：
文献类型：
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作者：
Ando, Hirofumi;Miyamoto, Tsutomu;Shiozawa, Tanri
虽然孕激素已被用于治疗子宫内膜增生和子宫内膜癌（EC），但其治疗效果有限。为了改善这一点，需要更详细地阐明的基础机制的影响，rexestin。在本研究中，我们研究了有丝分裂原诱导基因6（MIG 6），EGF受体的负调节，在孕激素介导的子宫内膜上皮细胞的生长抑制的参与。在正常子宫内膜和子宫内膜增生症患者经甲孕酮治疗后，MIG 6的免疫组化表达在分泌早期和中期升高。孕酮受体（PR）阳性EC细胞的孕酮（P4）的加入降低了生存力，诱导MIG 6信使RNA（mRNA）和蛋白质的表达。使用siRNA沉默MIG 6消除了P4介导的EC细胞活力的降低，表明MIG 6是PR介导的生长抑制的重要下游组分。为了增强PR驱动的信号，我们检查了组蛋白去乙酰化酶（HDAC）抑制剂的作用，因为组蛋白乙酰化已显示增加PR的表达。（帕比司他，LBH 589;帕比司他汀A，TSA;辛二酰苯胺异羟肟酸（SAHA）降低EC细胞活力并上调PR和MIG 6的表达，并且这些效果在LBH 589中最强。LBH 589和MPA的加入协同降低EC细胞的活力并增加细胞凋亡。这些结果表明，LBH 589具有通过上调PR和MIG 6而作为雷公藤多甙治疗的增强剂的潜力。
Although progestin has been used to treat endometrial hyperplasia and endometrial carcinoma (EC), its therapeutic efficacy is limited. In order to improve this, the underlining mechanisms of the effects of progestin need to be elucidated in more detail. In the present study, we examined the involvement of mitogen-inducible gene-6 (MIG6), a negative regulator of the EGF receptor, in the progestin-mediated growth suppression of endometrial epithelia. The immunohistochemical expression of MIG6 was elevated in the early to mid-secretory phases of normal endometrium and also with endometrial hyperplasia after medroxyprogesterone acetate (MPA) therapy. The addition of progesterone (P4) to progesterone receptor (PR)-positive EC cells reduced the viability and induced MIG6 messenger RNA (mRNA) and protein expression. The silencing of MIG6 using siRNA eliminated the P4-mediated reduction of EC cell viability, indicating that MIG6 is an essential downstream component of PR-mediated growth suppression. In order to enhance PR-driven signals, we examined the effects of histone deacetylase (HDAC) inhibitors because histone acetylation has been shown to increase the expression of PR. The addition of three HDAC inhibitors (panobinostat, LBH589; trichostatin A, TSA; suberoylanilide hydroxamic acid, SAHA) decreased the viability of EC cells and up-regulated the expression of PR and MIG6, and these effects were the strongest with LBH589. The addition of LBH589 and MPA synergistically decreased the viability and increased apoptosis in EC cells. These results indicate that LBH589 has potential as an enhancer of progestin therapy via the up-regulation of PR and MIG6.