Transient Receptor Potential Melastatin 8 (TRPM8) Channel Regulates Proliferation and Migration of Breast Cancer Cells by Activating the AMPK-ULK1 Pathway to Enhance Basal Autophagy.
Transient Receptor Potential Melastatin 8 (TRPM8) Channel Regulates Proliferation and Migration of Breast Cancer Cells by Activating the AMPK-ULK1 Pathway to Enhance Basal Autophagy.
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瞬时受体电位 Melastatin 8 (TRPM8) 通道通过激活 AMPK-ULK1 途径增强基础自噬来调节乳腺癌细胞的增殖和迁移。
DOI：
10.3389/fonc.2020.573127
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发表时间：
2020
影响因子：
4.7
通讯作者：
Tang J
中科院分区：
文献类型：
--
作者：
Huang Y;Li S;Jia Z;Zhao W;Zhou C;Zhang R;Ali DW;Michalak M;Chen XZ;Tang J
钙渗透性阳离子通道TRPM8（瞬时受体电位美拉他汀8）是阳离子通道TRP超家族的一员，在各种高水平自噬的癌症中上调，包括前列腺癌、胰腺癌、乳腺癌、肺癌和结肠癌。自噬受amp活化蛋白激酶（AMPK）的密切调控，通过降解细胞内结构产生营养物质，在肿瘤生长中起重要作用。此外，AMPK活性受细胞内Ca2+浓度的调节。考虑到TRPM8是一种非选择性Ca2+渗透性阳离子通道，在钙稳态中起关键作用，我们假设TRPM8可能通过控制AMPK活性，从而调节细胞自噬，调节乳腺癌细胞的增殖和迁移。在本研究中，在几种类型的哺乳动物癌细胞中，TRPM8过表达增强了基础自噬水平，而TRPM8敲低则降低了基础自噬水平。此外，TRPM8通道的活性调节了基础自噬的水平。TRPM8调控自噬的机制涉及自噬相关的信号通路，激活AMPK和ULK1以及吞噬细胞的形成。受损的AMPK破坏了trpm8依赖性的自噬调节。TRPM8与AMPK在蛋白复合物中相互作用，TRPM8的胞质c端介导TRPM8 - AMPK相互作用。最后，基底自噬介导TRPM8对乳腺癌细胞增殖和迁移的调控作用。因此，本研究确定了TRPM8作为癌细胞基础自噬的一种新型调节剂，通过与AMPK相互作用，进而激活AMPK，在TRPM8介导的乳腺癌进展的协调级联中激活ULK1。
The calcium-permeable cation channel TRPM8 (transient receptor potential melastatin 8) is a member of the TRP superfamily of cation channels that is upregulated in various types of cancer with high levels of autophagy, including prostate, pancreatic, breast, lung, and colon cancers. Autophagy is closely regulated by AMP-activated protein kinase (AMPK) and plays an important role in tumor growth by generating nutrients through degradation of intracellular structures. Additionally, AMPK activity is regulated by intracellular Ca2+ concentration. Considering that TRPM8 is a non-selective Ca2+-permeable cation channel and plays a key role in calcium homoeostasis, we hypothesized that TRPM8 may control AMPK activity thus modulating cellular autophagy to regulate the proliferation and migration of breast cancer cells. In this study, overexpression of TRPM8 enhanced the level of basal autophagy, whereas TRPM8 knockdown reduced the level of basal autophagy in several types of mammalian cancer cells. Moreover, the activity of the TRPM8 channel modulated the level of basal autophagy. The mechanism of regulation of autophagy by TRPM8 involves autophagy-associated signaling pathways for activation of AMPK and ULK1 and phagophore formation. Impaired AMPK abolished TRPM8-dependent regulation of autophagy. TRPM8 interacts with AMPK in a protein complex, and cytoplasmic C-terminus of TRPM8 mediates the TRPM8–AMPK interaction. Finally, basal autophagy mediates the regulatory effects of TRPM8 on the proliferation and migration of breast cancer cells. Thus, this study identifies TRPM8 as a novel regulator of basal autophagy in cancer cells acting by interacting with AMPK, which in turn activates AMPK to activate ULK1 in a coordinated cascade of TRPM8-mediated breast cancer progression.
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影响因子：
21.3
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影响因子：
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作者：
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DOI：
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