The CDK1/TFCP2L1/ID2 cascade offers a novel combination therapy strategy in a preclinical model of bladder cancer.
The CDK1/TFCP2L1/ID2 cascade offers a novel combination therapy strategy in a preclinical model of bladder cancer.
复制标题
DOI：
10.1038/s12276-022-00786-0
复制
发表时间：
2022-06
影响因子：
12.8
通讯作者：
Shin, Dong-Myung
中科院分区：
文献类型：
--
作者：
Heo, Jinbeom;Lee, Jinyoung;Nam, Yun Ji;Kim, YongHwan;Yun, HongDuck;Lee, Seungun;Ju, Hyein;Ryu, Chae-Min;Jeong, Seon Min;Lee, Jinwon;Lim, Jisun;Cho, Yong Mee;Jeong, Eui Man;Hong, Bumsik;Son, Jaekyoung;Shin, Dong-Myung
膀胱尿路上皮癌（BC）中胚胎发生相关分子程序的异常激活与致癌去分化和肿瘤转移相关的干性特征相关。最近，我们报道了转录因子CP 2样蛋白-1（TFCP 2L 1）的过表达及其在Thr 177处被细胞周期蛋白依赖性激酶-1（CDK 1）磷酸化在调节膀胱癌发生中起关键作用。然而，这种新型CDK 1-TFCP 2L 1分子网络的临床相关性和治疗潜力仍然难以捉摸。在这里，我们证明了DNA结合抑制剂-2（ID 2）作为一个重要的介质，作为TFCP 2L 1的直接抑制目标，以调节干细胞的特征和BC细胞的存活。低ID 2和高CDK 1表达与不利的临床特征显著相关。TFCP 2L 1通过直接结合其启动子区下调ID 2。与这些发现一致，ID 2的异位表达或用ID 2的化学活化剂芹菜素处理，触发凋亡并损害增殖，抑制干性特征，并降低BC细胞的侵袭能力。在原位BC异种移植动物模型中，用特异性CDK 1抑制剂RO-3306和芹菜素的组合治疗显著抑制肿瘤生长。本研究证明了ID 2作为CDK 1-TFCP 2L 1通路的直接靶标用于调节BC细胞的干细胞特征的生物学作用和临床实用性。芹菜素是一种在欧芹和甘菊等植物中发现的强效抗氧化剂，与一种抑制细胞周期蛋白CDK 1的药物联合治疗显示出开发膀胱癌（BC）疗法的希望。开启通常在干细胞中激活的基因可能导致癌症，包括BC。虽然已知CDK 1在BC细胞中激活这些基因之一，但没有发现抑制激活的方法。韩国蔚山大学医学院的Jinbeom Heo和同事研究了CDK 1在BC中的作用。他们发现由CDK 1激活的转录因子抑制了一种抑制干细胞样特征的蛋白质ID 2。在小鼠模型中，同时抑制CDK 1和用芹菜素加强ID 2强烈抑制肿瘤生长。这些结果有助于为BC患者开发新的治疗方案指明方向。
Aberrant activation of embryogenesis-related molecular programs in urothelial bladder cancer (BC) is associated with stemness features related to oncogenic dedifferentiation and tumor metastasis. Recently, we reported that overexpression of transcription factor CP2-like protein-1 (TFCP2L1) and its phosphorylation at Thr177 by cyclin-dependent kinase-1 (CDK1) play key roles in regulating bladder carcinogenesis. However, the clinical relevance and therapeutic potential of this novel CDK1-TFCP2L1 molecular network remain elusive. Here, we demonstrated that inhibitor of DNA binding-2 (ID2) functions as a crucial mediator by acting as a direct repressive target of TFCP2L1 to modulate the stemness features and survival of BC cells. Low ID2 and high CDK1 expression were significantly associated with unfavorable clinical characteristics. TFCP2L1 downregulated ID2 by directly binding to its promoter region. Consistent with these findings, ectopic expression of ID2 or treatment with apigenin, a chemical activator of ID2, triggered apoptosis and impaired the proliferation, suppressed the stemness features, and reduced the invasive capacity of BC cells. Combination treatment with the specific CDK1 inhibitor RO-3306 and apigenin significantly suppressed tumor growth in an orthotopic BC xenograft animal model. This study demonstrates the biological role and clinical utility of ID2 as a direct target of the CDK1-TFCP2L1 pathway for modulating the stemness features of BC cells. Combination therapy with apigenin, a powerful antioxidant found in plants such as parsley and camomile, and a drug that inhibits the cell cycle protein CDK1 shows promise for developing therapies for bladder cancer (BC). Switching on genes usually activated in stem cells can cause cancer, including BC. Although CDK1 was known to activate one of these genes in BC cells, no way to suppress the activation had been identified. Jinbeom Heo at University of Ulsan College of Medicine, South Korea, and coworkers investigated CDK1’s role in BC. They found that the transcription factor activated by CDK1 suppressed a protein, ID2, that suppressed stem cell-like characteristics. Simultaneously suppressing CDK1 and boosting ID2 with apigenin strongly repressed tumor growth in a mouse model. These results help point the way to developing new treatment options for BC patients.
登录
查看更多内容
影响因子：
50.3
作者：
Berger AH;Brooks AN;Wu X;Shrestha Y;Chouinard C;Piccioni F;Bagul M;Kamburov A;Imielinski M;Hogstrom L;Zhu C;Yang X;Pantel S;Sakai R;Watson J;Kaplan N;Campbell JD;Singh S;Root DE;Narayan R;Natoli T;Lahr DL;Tirosh I;Tamayo P;Getz G;Wong B;Doench J;Subramanian A;Golub TR;Meyerson M;Boehm JS
通讯作者：
Boehm JS
影响因子：
64.5
作者：
Malta TM;Sokolov A;Gentles AJ;Burzykowski T;Poisson L;Weinstein JN;Kamińska B;Huelsken J;Omberg L;Gevaert O;Colaprico A;Czerwińska P;Mazurek S;Mishra L;Heyn H;Krasnitz A;Godwin AK;Lazar AJ;Cancer Genome Atlas Research Network;Stuart JM;Hoadley KA;Laird PW;Noushmehr H;Wiznerowicz M
通讯作者：
Wiznerowicz M
影响因子：
8
作者：
Ahlqvist, K.;Saamarthy, K.;Massoumi, R.
通讯作者：
Massoumi, R.
影响因子：
4.8
作者：
Rockman, SP;Currie, SA;Phillips, WA
通讯作者：
Phillips, WA
ID蛋白质在发育和癌症相关的途径中。
DOI：
10.1186/s12964-016-0161-y
发表时间：
2017-01-25
期刊：
Cell communication and signaling : CCS
影响因子：
--
作者：
Roschger C;Cabrele C
通讯作者：
Cabrele C