Molecular targeting of protein arginine deiminases to suppress colitis and prevent colon cancer.
Molecular targeting of protein arginine deiminases to suppress colitis and prevent colon cancer.
复制标题
蛋白质精氨酸脱亚胺酶的分子靶向抑制结肠炎和预防结肠癌
DOI：
10.18632/oncotarget.5937
复制
发表时间：
2015-11-03
期刊：
影响因子：
--
通讯作者：
Hofseth LJ
中科院分区：
文献类型：
--
作者：
Witalison EE;Cui X;Causey CP;Thompson PR;Hofseth LJ
溃疡性结肠炎 (UC) 是一种慢性疾病，结肠内壁发炎并形成溃疡，导致腹痛、腹泻和直肠出血。这些症状的程度取决于疾病的严重程度。蛋白质精氨酸脱亚胺酶 (PAD) 家族通过瓜氨酸化将肽基精氨酸转化为肽基瓜氨酸。 PAD 失调，在许多疾病中出现异常瓜氨酸化，包括 UC 和结直肠癌 (CRC)。我们开发了小分子泛 PAD 抑制剂氯脒 (Cl-amidine)，具有多个目标，包括治疗 UC 和预防 CRC。我们最近的结果显示：1) Cl-脒在葡聚糖硫酸钠 (DSS) 小鼠模型中抑制体内结肠炎； 2）Cl-脒在体外诱导微小RNA（miR）-16导致细胞周期停滞，我们测试了Cl-脒可以预防肿瘤发生以及Cl-脒诱导miR-16可能参与体内的假设。与我们的假设一致，我们提供的证据表明，在我们的结肠炎相关 CRC 小鼠模型中，通过饮用水输送的 Cl-脒可以预防结肠肿瘤的发生，在该模型中，给小鼠注射致癌氧化偶氮甲烷 (AOM)，然后进行多个周期的 2% DSS 诱导结肠炎。为了开始确定机制，我们检查了 Cl-脒对 miR-16 的影响。结果显示，在结肠上皮细胞从结肠炎到癌症的过程中，miR-16 受到抑制，通过饮用 Cl-脒可以恢复这种抑制。同样，Cl-脒抑制 Ki67 和 miR-16 的细胞增殖靶标（细胞周期蛋白 D1 和 E1）。细胞增殖标志物的减少和肿瘤抑制 miRNA 表达的增加可能定义了 Cl-脒如何抑制体内肿瘤发生的机制。
Ulcerative colitis (UC) is a chronic disease, in which the lining of the colon becomes inflamed and develops ulcers leading to abdominal pain, diarrhea, and rectal bleeding. The extent of these symptoms depends on disease severity. The protein arginine deiminase (PAD) family of enzymes converts peptidyl-Arginine to peptidyl-Citrulline through citrullination. PADs are dysregulated, with abnormal citrullination in many diseases, including UC and colorectal cancer (CRC). We have developed the small molecule, pan-PAD inhibitor, Chlor-amidine (Cl-amidine), with multiple goals, including treating UC and preventing CRC. Building off our recent results showing that: 1) Cl-amidine suppresses colitis in vivo in a dextran sulfate sodium (DSS) mouse model; and 2) Cl-amidine induces microRNA (miR)-16 in vitro causing cell cycle arrest, we tested the hypothesis that Cl-amidine can prevent tumorigenesis and that miR-16 induction, by Cl-amidine, may be involved in vivo. Consistent with our hypothesis, we present evidence that Cl-amidine, delivered in the drinking water, prevents colon tumorigenesis in our mouse model of colitis-associated CRC where mice are given carcinogenic azoxymethane (AOM), followed by multiple cycles of 2% DSS to induce colitis. To begin identifying mechanisms, we examined the effects of Cl-amidine on miR-16. Results show miR-16 suppression during the colitis-to-cancer sequence in colon epithelial cells, which was rescued by drinking Cl-amidine. Likewise, Ki67 and cellular proliferation targets of miR-16 (Cyclins D1 and E1) were suppressed by Cl-amidine. The decrease in cell proliferation markers and increase in tumor suppressor miRNA expression potentially define a mechanism of how Cl-amidine is suppressing tumorigenesis in vivo.