Combination of AKT inhibition with autophagy blockade effectively reduces ascites-derived ovarian cancer cell viability
Combination of AKT inhibition with autophagy blockade effectively reduces ascites-derived ovarian cancer cell viability
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DOI：
10.1093/carcin/bgu049
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发表时间：
2014-09-01
期刊：
影响因子：
4.7
通讯作者：
Shepherd, Trevor G.
中科院分区：
文献类型：
--
作者：
Correa, Rohann J. M.;Valdes, Yudith Ramos;Shepherd, Trevor G.
最近对上皮性卵巢癌（EOC）的高级别浆液性亚型的基因组学分析显示，磷脂酰肌醇3-激酶（PI 3 K）/AKT通路的畸变导致信号活性上调。因此，PI 3 K/AKT通路代表了侵袭性高级别EOC的潜在治疗靶点。我们先前证明，用变构AKT抑制剂Akti-1/2处理恶性腹水衍生的原代人EOC细胞和卵巢癌细胞系诱导休眠样细胞生长抑制反应，但不降低细胞活力。在这份报告中，我们表明，在这些细胞中的变构AKT抑制诱导细胞保护性自噬。单独使用氯喹（CQ）或与Akti-1/2组合使用氯喹（CQ）抑制自噬导致活细胞数显著减少。事实上，与单独使用CQ相比，Akti-1/2通过在联合处理的细胞中表现出显著降低的EC 50值，使EOC细胞对CQ诱导的细胞死亡敏感。此外，我们评估了新的特异性和有效的自噬抑制剂-1（Spaadin-1）的作用，并证明Spaadin-1在原代EOC细胞和细胞系中以Beclin-1非依赖性方式抑制自噬。多细胞EOC球状体对Akti-1/2和CQ/Spaetin-1共治疗高度敏感，但对每种药物单独耐药。实际上，组合指数分析揭示了当两种试剂用于影响细胞活力时Akti-1/2和Spaetin-1之间的强协同作用; Akti-1/2和CQ共处理在大多数样品中也显示出协同作用。综上所述，我们提出AKT抑制和自噬阻断的组合将被证明有效地减少残留的EOC细胞，从而提供卵巢癌复发。
Recent genomics analysis of the high-grade serous subtype of epithelial ovarian cancer (EOC) show aberrations in the phosphatidylinositol 3-kinase (PI3K)/AKT pathway that result in upregulated signaling activity. Thus, the PI3K/AKT pathway represents a potential therapeutic target for aggressive high-grade EOC. We previously demonstrated that treatment of malignant ascites-derived primary human EOC cells and ovarian cancer cell lines with the allosteric AKT inhibitor Akti-1/2 induces a dormancy-like cytostatic response but does not reduce cell viability. In this report, we show that allosteric AKT inhibition in these cells induces cytoprotective autophagy. Inhibition of autophagy using chloroquine (CQ) alone or in combination with Akti-1/2 leads to a significant decrease in viable cell number. In fact, Akti-1/2 sensitizes EOC cells to CQ-induced cell death by exhibiting markedly reduced EC50 values in combination-treated cells compared with CQ alone. In addition, we evaluated the effects of the novel specific and potent autophagy inhibitor-1 (Spautin-1) and demonstrate that Spautin-1 inhibits autophagy in a Beclin-1-independent manner in primary EOC cells and cell lines. Multicellular EOC spheroids are highly sensitive to Akti-1/2 and CQ/Spautin-1 cotreatments, but resistant to each agent alone. Indeed, combination index analysis revealed strong synergy between Akti-1/2 and Spautin-1 when both agents were used to affect cell viability; Akti-1/2 and CQ cotreatment also displayed synergy in most samples. Taken together, we propose that combination AKT inhibition and autophagy blockade would prove efficacious to reduce residual EOC cells for supplying ovarian cancer recurrence.