Cranberry proanthocyanidins inhibit esophageal adenocarcinoma in vitro and in vivo through pleiotropic cell death induction and PI3K/AKT/mTOR inactivation.
Cranberry proanthocyanidins inhibit esophageal adenocarcinoma in vitro and in vivo through pleiotropic cell death induction and PI3K/AKT/mTOR inactivation.
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DOI：
10.18632/oncotarget.5586
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发表时间：
2015-10-20
期刊：
影响因子：
--
通讯作者：
Howell AB
中科院分区：
文献类型：
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作者：
Kresty LA;Weh KM;Zeyzus-Johns B;Perez LN;Howell AB
蔓越莓富含已知可改善泌尿道健康的生物活性成分，最近的证据支持蔓越莓具有抗癌特性。然而，蔓越莓抑制癌症的机制仍有待阐明，特别是在体内。利用酸敏感和耐酸的人食管腺癌（EAC）细胞系和无胸腺NU/NU小鼠的食管肿瘤异种移植物研究了纯化的蔓越莓衍生的原花青素提取物（C-PAC）的性质。C-PAC在酸敏感的JHAD 1和OE 33细胞中主要通过自噬和低水平的凋亡诱导caspase非依赖性细胞死亡，但在酸抗性的OE 19细胞中导致细胞坏死。同样，C-PAC诱导JHAD 1细胞坏死，通过反复暴露于酸化的胆汁鸡尾酒而达到耐酸性。C-PAC相关的细胞死亡涉及PI 3 K/AKT/mTOR失活、促凋亡蛋白诱导（BAX、BAK 1、脱酰胺BCL-xL、细胞色素C、PARP）、MAPK调节（P-P38/P-JNK）和体外G2-M期细胞周期阻滞。重要的是，C-PAC的口服递送通过调节AKT/mTOR/MAPK信号传导和诱导LC 3B的自噬形式来显著抑制OE 19肿瘤异种移植物生长，这首次支持了针对EAC的体内功效。C-PAC是EAC细胞死亡的强效诱导剂，并且在无毒行为可达到的浓度下在体内有效，有望在EAC风险增加的队列中进行预防性或治疗性干预，EAC是一种快速上升且极其致命的恶性肿瘤。
Cranberries are rich in bioactive constituents known to improve urinary tract health and more recent evidence supports cranberries possess cancer inhibitory properties. However, mechanisms of cancer inhibition by cranberries remain to be elucidated, particularly in vivo. Properties of a purified cranberry-derived proanthocyanidin extract (C-PAC) were investigated utilizing acid-sensitive and acid-resistant human esophageal adenocarcinoma (EAC) cell lines and esophageal tumor xenografts in athymic NU/NU mice. C-PAC induced caspase-independent cell death mainly via autophagy and low levels of apoptosis in acid-sensitive JHAD1 and OE33 cells, but resulted in cellular necrosis in acid-resistant OE19 cells. Similarly, C-PAC induced necrosis in JHAD1 cells pushed to acid-resistance via repeated exposures to an acidified bile cocktail. C-PAC associated cell death involved PI3K/AKT/mTOR inactivation, pro-apoptotic protein induction (BAX, BAK1, deamidated BCL-xL, Cytochrome C, PARP), modulation of MAPKs (P-P38/P-JNK) and G2-M cell cycle arrest in vitro. Importantly, oral delivery of C-PAC significantly inhibited OE19 tumor xenograft growth via modulation of AKT/mTOR/MAPK signaling and induction of the autophagic form of LC3B supporting in vivo efficacy against EAC for the first time. C-PAC is a potent inducer of EAC cell death and is efficacious in vivo at non-toxic behaviorally achievable concentrations, holding promise for preventive or therapeutic interventions in cohorts at increased risk for EAC, a rapidly rising and extremely deadly malignancy.