Zinc and p53 disrupt mitochondrial binding of HK2 by phosphorylating VDAC1
Zinc and p53 disrupt mitochondrial binding of HK2 by phosphorylating VDAC1
复制标题
锌和 p53 通过磷酸化 VDAC1 破坏 HK2 的线粒体结合
DOI：
10.1016/j.yexcr.2018.12.002
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发表时间：
2019-01-01
影响因子：
3.7
通讯作者：
Li, Yang
中科院分区：
文献类型：
--
作者：
Xue, Ya-Nan;Yu, Bing-Bing;Li, Yang
许多细胞死亡调节因子在物理上或功能上与代谢酶相互作用。这些相互作用从肿瘤细胞代谢和凋亡的角度提供了对抗癌治疗机制的见解。最近的研究表明，锌和p53不仅诱导肿瘤细胞凋亡，而且还调节肿瘤细胞的代谢。然而，潜在的机制是复杂的，仍然不清楚，使得进一步的研究势在必行，为未来的癌症治疗提供线索。在这项研究中，我们发现，己糖激酶2（HK2），它具有双重代谢和凋亡功能，是下游的锌和p53在前列腺癌患者组织和前列腺癌细胞系。值得注意的是，HK2的线粒体位置对其功能至关重要。我们证明锌和p53通过磷酸化VDAC 1破坏前列腺癌细胞中HK 2的线粒体结合，这是由蛋白激酶B（Akt）抑制和糖原合成酶激酶3 β（GSK 3 β）激活介导的。此外，我们发现锌与p53的组合显著抑制前列腺癌细胞异种移植模型中的肿瘤生长。因此，锌和p53干扰HK2的线粒体定位可能为癌症提供新的治疗方法。
Many cell death regulators physically or functionally interact with metabolic enzymes. These interactions provide insights into mechanisms of anticancer treatments from the perspective of tumor cell metabolism and apoptosis. Recent studies have shown that zinc and p53 not only induce tumor cell apoptosis, but also regulate tumor cell metabolism. However, the underlying mechanism is complex and remains unclear, making further research imperative to provide clues for future cancer treatments. In this study, we found that hexokinase 2 (HK2), which has dual metabolic and apoptotic functions, is downstream of zinc and p53 in both prostate cancer patient tissue and prostate cancer cell lines. Notably, the mitochondrial location of HK2 is crucial for its function. We demonstrate that zinc and p53 disrupt mitochondrial binding of HK2 in prostate cancer cells by phosphorylating VDAC1, which is mediated by protein kinase B (Akt) inhibition and glycogen synthase kinase 3 beta (GSK3 beta) activation. In addition, we found that zinc combined with p53 significantly inhibited tumor growth in a prostate cancer cell xenograft model. Therefore, interference of the mitochondrial localization of HK2 by zinc and p53 may provide a new treatment approach for cancer.