AKT inhibitor MK-2206 sensitizes breast cancer cells to MLN4924, a first-in-class NEDD8-activating enzyme (NAE) inhibitor
AKT inhibitor MK-2206 sensitizes breast cancer cells to MLN4924, a first-in-class NEDD8-activating enzyme (NAE) inhibitor
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AKT 抑制剂 MK-2206 使乳腺癌细胞对 MLN4924 敏感，MLN4924 是一种一流的 NEDD8 激活酶 (NAE) 抑制剂。
DOI：
10.1080/15384101.2018.1515550
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发表时间：
2018-01-01
期刊：
影响因子：
4.3
通讯作者：
Zhao, Yongchao
中科院分区：
文献类型：
--
作者：
Chen, Xiaoyu;Cui, Danrui;Zhao, Yongchao
乳腺癌是女性癌症患者中常见的癌症类型，也是癌症相关死亡的主要原因。在过去的几十年里，乳腺癌的靶向治疗得到了迅速发展。其中，MLN 4924是一种一流的NEDD 8激活酶（NAE）抑制剂，在许多研究中通过灭活cullin-RING连接酶并导致其底物蓄积以诱导细胞凋亡来发挥抗肿瘤活性。在本研究中，我们发现MLN 4924可激活HER 2阳性和三阴性乳腺癌（TNBC）细胞系中的AKT通路。鉴于AKT信号传导是某些类型癌症中肿瘤进展和耐药性的原因，我们假设AKT抑制剂可能协同增强MLN 4924对乳腺癌的肿瘤抑制能力。为了证明MK-2206的增敏作用，选择MK-2206作为辅助处理，检测细胞生长、迁移和凋亡。结果表明，MLN 4924处理可抑制SK-BR 3和MDA-MB 231乳腺癌细胞系的细胞生长和迁移，并诱导细胞凋亡。更重要的是，与MLN 4924单独给药相比，MLN 4924和MK-2206联合给药确实引起了更强的细胞毒性和迁移抑制，以及更高的细胞凋亡诱导。我们的研究为MLN 4924与AKT抑制剂的策略性药物组合提供了概念验证证据，可通过增强细胞凋亡最大限度地杀伤乳腺癌细胞。
Breast cancer is a common type of cancer among female cancer patients and the main cause of cancer-related deaths. During the last decades, targeted therapies for breast cancer have been rapidly developing. Among them, MLN4924, a first-in-class NEDD8-activating enzyme (NAE) inhibitor, has performed antitumor activity by inactivating the cullin-RING ligases and causing the accumulation of their substrates to induce apoptosis in a number of studies. In this study, we found that MLN4924 activates the AKT pathway in both HER2-positive and triple-negative breast cancer (TNBC) cell lines. Given that AKT signaling is responsible for tumor progression and drug resistance in some types of cancers, we hypothesized that the AKT inhibitor may synergistically enhance the tumor suppression capability in breast cancer by MLN4924. To demonstrate the sensitizing effect, MK-2206 was chosen as the adjuvant treatment, and cell growth, migration and apoptosis were detected. The results showed that MLN4924 treatment inhibited cell growth and migration and induced apoptosis in both SK-BR3 and MDA-MB231 breast cancer cell lines. More importantly, the combined treatment of MLN4924 and MK-2206 indeed caused stronger cytotoxicity and inhibition of migration and a much higher induction of apoptosis compared with MLN4924 treatment alone. Our study provides the proof-of-concept evidence for strategic drug combination of MLN4924 with an AKT inhibitor for maximal killing of breast cancer cells via the enhancement of apoptosis.