Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, 209 Tongshan Rd, Xuzhou, Jiangsu 221004, China.
Department of Anesthesiology, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226006, China.
Cancer Lett. 2022 Jan 28;525:179-197. doi: 10.1016/j.canlet.2021.10.043. Epub 2021 Nov 6.
The transient receptor potential melastatin-subfamily member 7 (TRPM7) is a ubiquitous cation channel possessing kinase activity. TRPM7 mediates a variety of physiological responses by conducting flow of cations such as Ca, Mg, and Zn. Here, we show that the activation of TRPM7 channel stimulated by chemical agonists of TRPM7, Clozapine or Naltriben, inhibited autophagy via mediating Zn release to the cytosol, presumably from the intracellular Zn-accumulating vesicles where TRPM7 localizes. Zn release following the activation of TRPM7 disrupted the fusion between autophagosomes and lysosomes by disturbing the interaction between Sxt17 and VAMP8 which determines fusion status of autophagosomes and lysosomes. Ultimately, the disrupted fusion resulting from stimulation of TRPM7 channels arrested autophagy. Functionally, we demonstrate that the autophagy inhibition mediated by TRPM7 triggered cell death and suppressed metastasis of cancer cells in vitro, more importantly, restricted tumor growth and metastasis in vivo, by evoking apoptosis, cell cycle arrest, and reactive oxygen species (ROS) elevation. These findings represent a strategy for stimulating TRPM7 to combat cancer.
瞬时受体电位 melastatin 亚家族成员 7（TRPM7）是一种普遍存在的阳离子通道，具有激酶活性。TRPM7 通过传导 Ca、Mg 和 Zn 等阳离子来介导多种生理反应。在这里，我们表明，TRPM7 通道的激活被 TRPM7 的化学激动剂氯氮平或萘替芬激活，通过将 Zn 释放到细胞质中来抑制自噬，可能是从 TRPM7 定位的细胞内 Zn 积累囊泡中释放出来的。TRPM7 激活后释放的 Zn 通过干扰决定自噬体和溶酶体融合状态的 Sxt17 和 VAMP8 之间的相互作用，破坏自噬体和溶酶体之间的融合。最终，TRPM7 通道的激活破坏融合，从而阻止自噬。在功能上，我们证明了由 TRPM7 介导的自噬抑制会触发细胞死亡，并抑制体外癌细胞的转移，更重要的是，通过诱导细胞凋亡、细胞周期停滞和活性氧（ROS）升高，在体内限制肿瘤生长和转移。这些发现代表了一种通过刺激 TRPM7 来对抗癌症的策略。
