The mechanism underlying the effects of the cell surface ATP synthase on the regulation of intracellular acidification during acidosis
The mechanism underlying the effects of the cell surface ATP synthase on the regulation of intracellular acidification during acidosis
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DOI：
10.1002/jcb.24511
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发表时间：
2013-07
影响因子：
4
通讯作者：
Wen-juan Wang;Xiaoxin Shi;Yi-wen Liu;Yi-qing He;Ying-zhi Wang;Cuixia Yang;F. Gao
中科院分区：
文献类型：
--
作者：
Wen-juan Wang;Xiaoxin Shi;Yi-wen Liu;Yi-qing He;Ying-zhi Wang;Cuixia Yang;F. Gao
F1F0 -ATP合酶近来已成为抗癌研究的焦点。人们曾一度认为ATP合酶严格定位于线粒体内膜；然而，1994年发现，部分ATP合酶定位于细胞表面。细胞表面的ATP合酶参与血管生成、脂蛋白代谢、先天免疫、高血压、食物摄取调节等过程。据报道，这种合酶的抑制剂具有细胞毒性并能诱导细胞内酸化。然而，这些作用的介导机制以及涉及的分子途径仍不明确。在本研究中，我们旨在确定细胞表面ATP合酶抑制剂所诱导的细胞增殖抑制和细胞凋亡诱导是否与细胞内酸化有关，并探究这种抑制作用背后的机制，尤其是在酸性肿瘤环境中。我们证明，细胞内酸化有助于细胞表面ATP合酶抑制剂介导的细胞增殖抑制，但与细胞凋亡诱导无关。细胞内酸化只是靶向细胞表面ATP合酶的抗肿瘤药物的作用机制之一。我们提出，在细胞表面ATP合酶被其抑制剂阻断后，细胞内酸化与细胞表面ATP生成的抑制共同诱导细胞凋亡。更好地理解靶向细胞表面ATP合酶的癌症治疗所激活的机制，可能有助于开发有效的抗肿瘤疗法，这些疗法以该酶为靶点且不存在临床局限性。《细胞生物化学杂志》2013年第114卷第1695 - 1703页。© 2013 威利期刊出版公司。
The F1F0 ATP synthase has recently become the focus of anti‐cancer research. It was once thought that ATP synthases were located strictly on the inner mitochondrial membrane; however, in 1994, it was found that some ATP synthases localized to the cell surface. The cell surface ATP synthases are involved in angiogenesis, lipoprotein metabolism, innate immunity, hypertension, the regulation of food intake, and other processes. Inhibitors of this synthase have been reported to be cytotoxic and to induce intracellular acidification. However, the mechanisms by which these effects are mediated and the molecular pathways that are involved remain unclear. In this study, we aimed to determine whether the inhibition of cell proliferation and the induction of cell apoptosis that are induced by inhibitors of the cell surface ATP synthase are associated with intracellular acidification and to investigate the mechanism that underlines the effects of this inhibition, particularly in an acidic tumor environment. We demonstrated that intracellular acidification contributes to the cell proliferation inhibition that is mediated by cell surface ATP synthase inhibitors, but not to the induction of apoptosis. Intracellular acidification is only one of the mechanisms of ecto‐ATP synthase‐targeted antitumor drugs. We propose that intracellular acidification in combination with the inhibition of cell surface ATP generation induce cell apoptosis after cell surface ATP synthase blocked by its inhibitors. A better understanding of the mechanisms activated by ecto‐ATP synthase‐targeted cancer therapies may facilitate the development of potent anti‐tumor therapies, which target this enzyme and do not exhibit clinical limitations. J. Cell. Biochem. 114: 1695–1703, 2013. © 2013 Wiley Periodicals, Inc.