TNK2/ACK1-mediated phosphorylation of ATP5F1A (ATP synthase F1 subunit alpha) selectively augments survival of prostate cancer while engendering mitochondrial vulnerability.
TNK2/ACK1-mediated phosphorylation of ATP5F1A (ATP synthase F1 subunit alpha) selectively augments survival of prostate cancer while engendering mitochondrial vulnerability.
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DOI：
10.1080/15548627.2022.2103961
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发表时间：
2023-03
期刊：
影响因子：
13.3
通讯作者：
Mahajan, Nupam P.
中科院分区：
文献类型：
--
作者：
Chouhan, Surbhi;Sawant, Mithila;Weimholt, Cody;Luo, Jingqin;Sprung, Robert W.;Terrado, Mailyn;Mueller, David M.;Earp, H. Shelton;Mahajan, Nupam P.
关键词：
快速大分子合成的挑战迫使能量饥渴的癌细胞线粒体通过致癌酪氨酸激酶的激活来转换其代谢表型。激酶活性如何被癌细胞线粒体直接利用以满足高能量需求的确切方式仍有待破译。在这里，我们表明，非受体酪氨酸激酶，TNK 2/ACK 1（酪氨酸激酶非受体2），磷酸化ATP 5 F1 A（ATP合成酶F1亚基α）在Tyr 243和Tyr 246（Tyr 200和203在成熟蛋白，分别），不仅增加了复合物V的稳定性，而且还增加了癌细胞中的线粒体能量输出。此外，磷酸化ATP 5 F1 A（p-Y-ATP 5 F1 A）阻止其与其生理抑制剂ATP 5IF 1（ATP合成酶抑制因子亚基1）结合，从而引起持续的线粒体活性以促进癌细胞生长。TNK 2抑制剂（R）-9b逆转了这一过程，并诱导基于线粒体自噬的自噬，以减轻前列腺肿瘤的生长，同时保留正常的前列腺细胞。此外，（R）-9b介导的线粒体吞噬反应和肿瘤生长需要p-Y-ATP 5 F1 A的耗尽。此外，Tnk 2转基因小鼠显示增加的p-Y-ATP 5 F1 A和线粒体自噬的损失，并表现出前列腺上皮内瘤形成（PIN）。与这些数据一致，随着前列腺癌进展到恶性阶段，观察到p-Y-ATP 5 F1 A的显著增加。总的来说，这项研究揭示了酪氨酸激酶介导的线粒体能量调节作为一种独特的癌细胞线粒体脆弱性的分子复杂性，并提供了证据表明，TNK 2抑制剂可以作为“mitocans”诱导癌症特异性线粒体自噬。缩略语：ATP5F1A：ATP合酶F1亚基α; ATP 5IF 1：ATP合酶抑制因子亚基1; CRPC：去势抵抗性前列腺癌; DNM 1 L：发动蛋白1样; MAP 1 LC 3B/LC 3B：微管相关蛋白1轻链3 β; Mdivi-1：线粒体分裂抑制剂1; Mut-ATP 5 F1 A：ATP 5 F1 A的Y243，246 A突变体; OXPHOS：氧化磷酸化; PC：前列腺癌; PINK 1：PTEN诱导的激酶1; p-Y-ATP 5 F1 A：ATP 5 F1 A上磷酸化的酪氨酸243和246; TNK 2/ACK 1：酪氨酸激酶非受体2; Ub：泛素; WT：野生型
The challenge of rapid macromolecular synthesis enforces the energy-hungry cancer cell mitochondria to switch their metabolic phenotypes, accomplished by activation of oncogenic tyrosine kinases. Precisely how kinase activity is directly exploited by cancer cell mitochondria to meet high-energy demand, remains to be deciphered. Here we show that a non-receptor tyrosine kinase, TNK2/ACK1 (tyrosine kinase non receptor 2), phosphorylated ATP5F1A (ATP synthase F1 subunit alpha) at Tyr243 and Tyr246 (Tyr200 and 203 in the mature protein, respectively) that not only increased the stability of complex V, but also increased mitochondrial energy output in cancer cells. Further, phospho-ATP5F1A (p-Y-ATP5F1A) prevented its binding to its physiological inhibitor, ATP5IF1 (ATP synthase inhibitory factor subunit 1), causing sustained mitochondrial activity to promote cancer cell growth. TNK2 inhibitor, (R)-9b reversed this process and induced mitophagy-based autophagy to mitigate prostate tumor growth while sparing normal prostate cells. Further, depletion of p-Y-ATP5F1A was needed for (R)-9b-mediated mitophagic response and tumor growth. Moreover, Tnk2 transgenic mice displayed increased p-Y-ATP5F1A and loss of mitophagy and exhibited formation of prostatic intraepithelial neoplasia (PINs). Consistent with these data, a marked increase in p-Y-ATP5F1A was seen as prostate cancer progressed to the malignant stage. Overall, this study uncovered the molecular intricacy of tyrosine kinase-mediated mitochondrial energy regulation as a distinct cancer cell mitochondrial vulnerability and provided evidence that TNK2 inhibitors can act as “mitocans” to induce cancer-specific mitophagy. Abbreviations: ATP5F1A: ATP synthase F1 subunit alpha; ATP5IF1: ATP synthase inhibitory factor subunit 1; CRPC: castration-resistant prostate cancer; DNM1L: dynamin 1 like; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; Mdivi-1: mitochondrial division inhibitor 1; Mut-ATP5F1A: Y243,246A mutant of ATP5F1A; OXPHOS: oxidative phosphorylation; PC: prostate cancer; PINK1: PTEN induced kinase 1; p-Y-ATP5F1A: phosphorylated tyrosine 243 and 246 on ATP5F1A; TNK2/ACK1: tyrosine kinase non receptor 2; Ub: ubiquitin; WT: wild type
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影响因子：
16.6
作者：
Hopkins JF;Sabelnykova VY;Weischenfeldt J;Simon R;Aguiar JA;Alkallas R;Heisler LE;Zhang J;Watson JD;Chua MLK;Fraser M;Favero F;Lawerenz C;Plass C;Sauter G;McPherson JD;van der Kwast T;Korbel J;Schlomm T;Bristow RG;Boutros PC
通讯作者：
Boutros PC
影响因子：
16.6
作者：
Anderson GR;Wardell SE;Cakir M;Yip C;Ahn YR;Ali M;Yllanes AP;Chao CA;McDonnell DP;Wood KC
通讯作者：
Wood KC
影响因子：
46.9
作者：
通讯作者：
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影响因子：
8
作者：
Buchwald, M.;Pietschmann, K.;Brand, P.;Guenther, A.;Mahajan, N. P.;Heinzel, T.;Kraemer, O. H.
通讯作者：
Kraemer, O. H.
影响因子：
4.7
作者：
Eidelman E;Twum-Ampofo J;Ansari J;Siddiqui MM
通讯作者：
Siddiqui MM