Antitumor activity of potent pyruvate dehydrogenase kinase 4 inhibitors from plants in pancreatic cancer
Antitumor activity of potent pyruvate dehydrogenase kinase 4 inhibitors from plants in pancreatic cancer
复制标题
DOI：
10.1002/mc.23045
复制
发表时间：
2019-10-01
影响因子：
4.6
通讯作者：
Inoue, Hirokazu
中科院分区：
文献类型：
--
作者：
Tambe, Yukihiro;Terado, Tokio;Inoue, Hirokazu
丙酮酸脱氢酶激酶4（PDK 4）4磷酸化丙酮酸脱氢酶抑制其诱导糖酵解转变的能力。PDK 4表达在各种癌组织中频繁上调，其升高对于诱导瓦尔堡效应至关重要。鉴于PDK 4对改变葡萄糖代谢的作用，PDK 4是癌症治疗的有吸引力的靶标。以前的研究强调了确定一种有效化合物在亚微摩尔浓度下抑制PDK 4活性的必要性。在这里，我们鉴定了在低微摩尔浓度下抑制PDK 4的天然二萜醌（KIS化合物）。KIS 37（隐丹参酮）抑制KRAS激活的人胰腺癌细胞系（MIAPaCa-2和Panc-1）和结直肠癌细胞系（DLD-1和HCT 116）的三维球体和软琼脂集落形成试验中的锚定非依赖性生长。KIS 37还抑制这些细胞系中的KRAS蛋白表达。此外，在非贴壁培养条件下，KIS 37通过PI 3 K-Akt-mTOR信号通路抑制Rb蛋白和细胞周期蛋白D1蛋白表达的磷酸化，并抑制MIAPaCa-2细胞中癌症干细胞标志物CD 44、EpCAM和ALDH 1A 1的表达。KIS 37在40 mg/kg（腹膜内剂量）下还抑制了裸鼠皮下异种移植物和原位胰腺肿瘤模型中的胰腺癌细胞生长，而没有任何明显的毒性。在KIS 37处理的胰腺肿瘤中观察到ALDH 1A 1表达降低，表明癌细胞的干细胞性在原位肿瘤模型中也被抑制。上述结果表明，KIS 37给药是一种在KRAS激活的难治性人胰腺癌中靶向PDK 4的新治疗策略。
Phosphorylation of pyruvate dehydrogenase by pyruvate dehydrogenase kinase 4 (PDK4) 4 inhibits its ability to induce a glycolytic shift. PDK4 expression is frequently upregulated in various cancer tissues, with its elevation being critical for the induction of the Warburg effect. PDK4 is an attractive target for cancer therapy given its effect on shifting glucose metabolism. Previous research has highlighted the necessity of identifying a potent compound to suppress PDK4 activity at the submicromolar concentrations. Here we identified natural diterpene quinones (KIS compounds) that inhibit PDK4 at low micromolar concentrations. KIS37 (cryptotanshinone) inhibited anchorage-independent growth in three-dimensional spheroid and soft agar colony formation assays of KRAS-activated human pancreatic (MIAPaCa-2 and Panc-1) and colorectal (DLD-1 and HCT116) cancer cell lines. KIS37 also suppressed KRAS protein expression in such cell lines. Furthermore, KIS37 suppressed phosphorylation of Rb protein and cyclin D1 protein expression via the PI3K-Akt-mTOR signaling pathway under nonadherent culture conditions and suppressed the expression of cancer stem cell markers CD44, EpCAM, and ALDH1A1 in MIAPaCa-2 cells. KIS37 also suppressed pancreatic cancer cell growth in both subcutaneous xenograft and orthotopic pancreatic tumor models in nude mice at 40 mg/kg (intraperitoneal dose) without any evident toxicity. Reduced ALDH1A1 expression was observed in KIS37-treated pancreatic tumors, suggesting that cancer cell stemness was also suppressed in the orthotopic tumor model. The aforementioned results indicate that KIS37 administration is a novel therapeutic strategy for targeting PDK4 in KRAS-activated intractable human pancreatic cancer.