Targeting DCLK1 overcomes 5-fluorouracil resistance in colorectal cancer through inhibiting CCAR1/β-catenin pathway-mediated cancer stemness.
Targeting DCLK1 overcomes 5-fluorouracil resistance in colorectal cancer through inhibiting CCAR1/β-catenin pathway-mediated cancer stemness.
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靶向 DCLK1 通过抑制 CCAR1/β-catenin 通路介导的癌症干性克服结直肠癌中的 5-氟尿嘧啶耐药性
DOI：
10.1002/ctm2.743
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发表时间：
2022-05
影响因子：
10.6
通讯作者：
Zhang, Dejun
中科院分区：
文献类型：
--
作者：
Wang, Lanqing;Zhao, Lei;Lin, Zhenyu;Yu, Dandan;Jin, Min;Zhou, Pengfei;Ren, Jinghua;Cheng, Jing;Yang, Kunyu;Wu, Gang;Zhang, Tao;Zhang, Dejun
迄今为止，基于 5-氟尿嘧啶的化疗对于局部晚期或转移性结直肠癌 (CRC) 非常重要。然而化疗耐药导致肿瘤复发和转移，这是结直肠癌治疗的主要障碍。在当前的研究中，我们建立了 5-氟尿嘧啶耐药细胞系，并探索了结直肠癌中与 5-氟尿嘧啶耐药相关的潜在靶点。此外，我们还开展临床标本研究、体内外实验和分子机制研究，揭示DCLK1促进5氟尿嘧啶耐药的生物学效应和机制，阐明DCLK1作为结直肠癌5氟尿嘧啶耐药靶点的潜在临床价值。我们发现双皮质素样激酶 1 (DCLK1) 是一种癌症干细胞标记物，与 5-氟尿嘧啶耐药性相关，并且在功能上促进 CRC 中的癌症干性和 5-氟尿嘧啶耐药性。从机制上讲，我们阐明了 DCLK1 通过 C 末端结构域与细胞周期和凋亡调节因子 1 (CCAR1) 相互作用，并在 Ser343 位点磷酸化 CCAR1，这对于 CCAR1 稳定至关重要。此外，我们发现 DCLK1 通过 CCAR1 正向调节 β-catenin 信号传导，从而负责维持癌症干细胞性。随后，我们证明阻断 β-连环蛋白可以抑制 CRC 细胞中 DCLK1 介导的 5-氟尿嘧啶耐药性。重要的是，我们证明 DCLK1 抑制剂可以阻断 CCAR1/β-catenin 通路介导的癌症干细胞，从而在体外和体内抑制 5-氟尿嘧啶耐药的 CRC 细胞。总的来说，我们的研究结果表明，DCLK1 通过 CCAR1/β-catenin 通路介导的癌症干细胞促进 CRC 5-氟尿嘧啶耐药，并表明靶向 DCLK1 可能是消除癌症干细胞以克服 CRC 5-氟尿嘧啶耐药的有前途的方法。 DCLK1 是一种癌症干细胞标记物，与 5-氟尿嘧啶耐药性相关。 DCLK1 与 CCAR1 相互作用，并在 Ser343 位点磷酸化 CCAR1，这对于 CCAR1 的稳定至关重要。 DCLK1 通过 CCAR1/β-catenin 通路介导的癌症干性促进 5-氟尿嘧啶耐药。靶向 DCLK1 可能是一种消除癌症干细胞以克服 CRC 5-氟尿嘧啶耐药性的有前途的方法。
To date, 5‐fluorouracil‐based chemotherapy is very important for locally advanced or metastatic colorectal cancer (CRC). However, chemotherapy resistance results in tumor recurrence and metastasis, which is a major obstacle for treatment of CRC. In the current research, we establish 5‐fluorouracil resistant cell lines and explore the potential targets associated with 5‐fluorouracil resistance in CRC. Moreover, we perform clinical specimen research, in vitro and in vivo experiments and molecular mechanism research, to reveal the biological effects and the mechanism of DCLK1 promoting 5‐fluorouracil resistance, and to clarify the potential clinical value of DCLK1 as a target of 5‐fluorouracil resistance in CRC. We discover that doublecortin‐like kinase 1 (DCLK1), a cancer stem cell maker, is correlated with 5‐fluorouracil resistance, and functionally promotes cancer stemness and 5‐fluorouracil resistance in CRC. Mechanistically, we elucidate that DCLK1 interacts with cell cycle and apoptosis regulator 1 (CCAR1) through the C‐terminal domain, and phosphorylates CCAR1 at the Ser343 site, which is essential for CCAR1 stabilisation. Moreover, we find that DCLK1 positively regulates β‐catenin signalling via CCAR1, which is responsible for maintaining cancer stemness. Subsequently, we prove that blocking β‐catenin inhibits DCLK1‐mediated 5‐fluorouracil resistance in CRC cells. Importantly, we demonstrate that DCLK1 inhibitor could block CCAR1/β‐catenin pathway‐mediated cancer stemness and consequently suppresses 5‐fluorouracil resistant CRC cells in vitro and in vivo. Collectively, our findings reveal that DCLK1 promotes 5‐fluorouracil resistance in CRC by CCAR1/β‐catenin pathway‐mediated cancer stemness, and suggest that targeting DCLK1 might be a promising method to eliminate cancer stem cells for overcoming 5‐fluorouracil resistance in CRC. DCLK1, a cancer stem cell maker, is correlated with 5‐fluorouracil resistance. DCLK1 interacts with CCAR1 and phosphorylates CCAR1 at the Ser343 site, which is essential for CCAR1 stabilisation. DCLK1 promotes 5‐fluorouracil resistance by CCAR1/β‐catenin pathway‐mediated cancer stemness. Targeting DCLK1 might be a promising method to eliminate cancer stem cells for overcoming 5‐fluorouracil resistance in CRC.
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影响因子：
4.8
作者：
Ohmae, Shogo;Takemoto-Kimura, Sayaka;Bito, Haruhiko
通讯作者：
Bito, Haruhiko
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影响因子：
4
作者：
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影响因子：
2.6
作者：
Kadletz, Lorenz;Aumayr, Klaus;Lill, Claudia
通讯作者：
Lill, Claudia
影响因子：
3.1
作者：
Kalantari, Elham;Lari, Mohammad Hossein Asadi;Madjd, Zahra
通讯作者：
Madjd, Zahra
影响因子：
2.9
作者：
Fan, Mengjiao;Qian, Niansong;Dai, Guanghai
通讯作者：
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