Repurposing Niclosamide for Targeting Pancreatic Cancer by Inhibiting Hh/Gli Non-Canonical Axis of Gsk3β.
Repurposing Niclosamide for Targeting Pancreatic Cancer by Inhibiting Hh/Gli Non-Canonical Axis of Gsk3β.
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DOI：
10.3390/cancers13133105
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发表时间：
2021-06-22
期刊：
影响因子：
5.2
通讯作者：
Rachagani S
中科院分区：
文献类型：
--
作者：
Kaushal JB;Bhatia R;Kanchan RK;Raut P;Mallapragada S;Ly QP;Batra SK;Rachagani S
当前发现癌症治疗新药的障碍需要开发药物再利用的替代策略，即为已批准或正在研究的药物确定用于新治疗目的的新用途。氯硝柳胺 (Nic) 是一种经美国食品和药物管理局 (FDA) 批准的抗蠕虫药物，据报道具有抗癌作用，并正在各种临床试验中进行评估。在当前的研究中，我们评估了 Nic 对胰腺癌（PC）的体外治疗效果。我们的结果表明，线粒体应激和 mTORC1 依赖性自噬是 Nic 诱导 PC 细胞死亡的主要因素。这项研究通过增加调节分子信号传导的p-Gsk3β，包括抑制hedgehog (Hh)信号介导的细胞增殖和通过mTORC1依赖性自噬增加细胞凋亡，为Nic的抗癌功效提供了新的机制见解，可能有助于新型PC疗法的开发。氯硝柳胺 (Nic) 是 FDA 批准的驱虫药，据报道具有抗癌功效，目前正在针对各种实体瘤的临床试验中进行评估。基于其靶向多种信号通路的能力，在本研究中，我们评估了 Nic 对胰腺癌（PC）的体外治疗效果。我们观察到该药物的抗癌作用，如 G0/G1 期细胞周期停滞、抑制 PC 细胞活力、集落形成和迁移。我们的结果揭示了线粒体应激和 mTORC1 依赖性自噬是 Nic 诱导 PC 细胞死亡的主要因素。在选择性自噬抑制剂 spautin-1 存在下，Nic 诱导的活性氧 (ROS) 和细胞死亡显着减少，证明自噬是 Nic 介导的细胞死亡的主要贡献者。从机制上讲，Nic 抑制 BCL2 和 Beclin-1 之间的相互作用，从而支持自噬和细胞凋亡的串扰。此外，Nic 处理通过磷酸化其 Ser-9 残基导致 Gsk3β 失活，导致 Sufu 和 Gli3 上调，从而对 Hedgehog 信号传导和细胞存活产生负面影响。 Nic 诱导自噬细胞死亡，并且 Gsk3β 激活剂 LY-294002 通过挽救 Nic 处理后 Hh 信号传导的失活进一步证实了 p-Gsk3b 介导的 Sufu/Gli3 级联。这些结果表明涉及 Hh 信号传导的非经典机制，其中 p-Gsk3β 充当 Hh/Gli1 级联的负调节因子和自噬介导的细胞死亡的正调节因子。总体而言，这项研究通过靶向 p-Gsk3β 介导的非经典 Hh 信号传导并促进 mTORC1 依赖性自噬和细胞死亡，确定了 Nic 对 PC 的治疗功效。
The current obstacles for discovering new drugs for cancer therapy have necessitated the development of the alternative strategy of drug repurposing, the identification of new uses for approved or investigational drugs for new therapeutic purposes. Niclosamide (Nic) is a Food and Drug Administration (FDA)-approved anti-helminthic drug, reported to have anti-cancer effects, and is being assessed in various clinical trials. In the current study, we assessed the therapeutic efficacy of Nic on pancreatic cancer (PC) in vitro. Our results revealed mitochondrial stress and mTORC1-dependent autophagy as the predominant players of Nic-induced PC cell death. This study provided a novel mechanistic insight for anti-cancer efficacy of Nic by increasing p-Gsk3β that modulates molecular signaling(s), including inhibition of hedgehog (Hh) signaling-mediated cellular proliferation and increased apoptosis through mTORC1-dependent autophagy may prove helpful for the development of novel PC therapies. Niclosamide (Nic), an FDA-approved anthelmintic drug, is reported to have anti-cancer efficacy and is being assessed in clinical trials for various solid tumors. Based on its ability to target multiple signaling pathways, in the present study, we evaluated the therapeutic efficacy of Nic on pancreatic cancer (PC) in vitro. We observed an anti-cancerous effect of this drug as shown by the G0/G1 phase cell cycle arrest, inhibition of PC cell viability, colony formation, and migration. Our results revealed the involvement of mitochondrial stress and mTORC1-dependent autophagy as the predominant players of Nic-induced PC cell death. Significant reduction of Nic-induced reactive oxygen species (ROS) and cell death in the presence of a selective autophagy inhibitor spautin-1 demonstrated autophagy as a major contributor to Nic-mediated cell death. Mechanistically, Nic inhibited the interaction between BCL2 and Beclin-1 that supported the crosstalk of autophagy and apoptosis. Further, Nic treatment resulted in Gsk3β inactivation by phosphorylating its Ser-9 residue leading to upregulation of Sufu and Gli3, thereby negatively impacting hedgehog signaling and cell survival. Nic induced autophagic cell death, and p-Gsk3b mediated Sufu/Gli3 cascade was further confirmed by Gsk3β activator, LY-294002, by rescuing inactivation of Hh signaling upon Nic treatment. These results suggested the involvement of a non-canonical mechanism of Hh signaling, where p-Gsk3β acts as a negative regulator of Hh/Gli1 cascade and a positive regulator of autophagy-mediated cell death. Overall, this study established the therapeutic efficacy of Nic for PC by targeting p-Gsk3β mediated non-canonical Hh signaling and promoting mTORC1-dependent autophagy and cell death.
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