Small molecule kinase inhibitor LRRK2-IN-1 demonstrates potent activity against colorectal and pancreatic cancer through inhibition of doublecortin-like kinase 1.
Small molecule kinase inhibitor LRRK2-IN-1 demonstrates potent activity against colorectal and pancreatic cancer through inhibition of doublecortin-like kinase 1.
复制标题
DOI：
10.1186/1476-4598-13-103
复制
发表时间：
2014-05-06
期刊：
影响因子：
37.3
通讯作者：
Houchen CW
中科院分区：
文献类型：
--
作者：
Weygant N;Qu D;Berry WL;May R;Chandrakesan P;Owen DB;Sureban SM;Ali N;Janknecht R;Houchen CW
双重皮质醇样激酶1(DCLK1)是结直肠癌和胰腺癌的一种肿瘤特异性干细胞标记物。以前的体外和体内研究已经证明了用小干扰RNA(SiRNA)抑制DCLK1以及基因靶向DCLK1+细胞缺失的治疗效果。然而，抑制DCLK1激酶活性的作用尚未被直接研究。因此，我们评估了使用新型小分子激酶抑制剂LRRK2-IN-1抑制DCLK1激酶活性的效果，LRRK2-IN-1与DCLK1具有显著的亲和力。在此，我们报道了LRRK2-IN-1具有强大的抗癌活性，包括抑制癌细胞的增殖、迁移和侵袭，以及诱导细胞凋亡和细胞周期停滞。此外，我们还发现它在分子水平上调节干细胞、上皮-间充质转化和致癌靶点。此外，我们还发现LRRK2-IN-1抑制了DCLK1的活性和下游的DCLK1效应子c-myc，并且证明了DCLK1的活性是抵抗LRRK2-IN-1的一个重要因素。鉴于DCLK1的S肿瘤干细胞标记物的地位，对其在胃肠道肿瘤中的生物学作用和相互作用的深入了解可能会导致改善患者预后的发现。这项研究的结果表明，DCLK1激酶的小分子抑制剂应该进一步研究，因为它们可能有望成为抗肿瘤干细胞药物。
Doublecortin-like kinase 1 (DCLK1) is emerging as a tumor specific stem cell marker in colorectal and pancreatic cancer. Previous in vitro and in vivo studies have demonstrated the therapeutic effects of inhibiting DCLK1 with small interfering RNA (siRNA) as well as genetically targeting the DCLK1+ cell for deletion. However, the effects of inhibiting DCLK1 kinase activity have not been studied directly. Therefore, we assessed the effects of inhibiting DCLK1 kinase activity using the novel small molecule kinase inhibitor, LRRK2-IN-1, which demonstrates significant affinity for DCLK1. Here we report that LRRK2-IN-1 demonstrates potent anti-cancer activity including inhibition of cancer cell proliferation, migration, and invasion as well as induction of apoptosis and cell cycle arrest. Additionally we found that it regulates stemness, epithelial-mesenchymal transition, and oncogenic targets on the molecular level. Moreover, we show that LRRK2-IN-1 suppresses DCLK1 kinase activity and downstream DCLK1 effector c-MYC, and demonstrate that DCLK1 kinase activity is a significant factor in resistance to LRRK2-IN-1. Given DCLK1’s tumor stem cell marker status, a strong understanding of its biological role and interactions in gastrointestinal tumors may lead to discoveries that improve patient outcomes. The results of this study suggest that small molecule inhibitors of DCLK1 kinase should be further investigated as they may hold promise as anti-tumor stem cell drugs.
登录
查看更多内容
影响因子：
64.8
作者：
Liu, Guang-Hui;Qu, Jing;Suzuki, Keiichiro;Nivet, Emmanuel;Li, Mo;Montserrat, Nuria;Yi, Fei;Xu, Xiuling;Ruiz, Sergio;Zhang, Weiqi;Wagner, Ulrich;Kim, Audrey;Ren, Bing;Li, Ying;Goebl, April;Kim, Jessica;Soligalla, Rupa Devi;Dubova, Ilir;Thompson, James;Yates, John, III;Esteban, Concepcion Rodriguez;Sancho-Martinez, Ignacio;Izpisua Belmonte, Juan Carlos
通讯作者：
Izpisua Belmonte, Juan Carlos
影响因子：
158.5
作者：
Llovet, Josep M.;Ricci, Sergio;Bruix, Jordi
通讯作者：
Bruix, Jordi
影响因子：
10.3
作者：
Gambacorti-Passerini, Carlo;Antolini, Laura;Kim, Dong-Wook
通讯作者：
Kim, Dong-Wook
影响因子：
3.7
作者：
Leushacke M;Spörle R;Bernemann C;Brouwer-Lehmitz A;Fritzmann J;Theis M;Buchholz F;Herrmann BG;Morkel M
通讯作者：
Morkel M
影响因子：
4.5
作者：
Jürchott K;Kuban RJ;Krech T;Blüthgen N;Stein U;Walther W;Friese C;Kiełbasa SM;Ungethüm U;Lund P;Knösel T;Kemmner W;Morkel M;Fritzmann J;Schlag PM;Birchmeier W;Krueger T;Sperling S;Sers C;Royer HD;Herzel H;Schäfer R
通讯作者：
Schäfer R