Department of Pharmacology, School of Medicine, University of Colorado Anshutz Medical Campus, Aurora, Colorado.
Pharmacology Graduate Program, University of Colorado Anshutz Medical Campus, Aurora, Colorado.
Mol Cancer Res. 2022 Apr 1;20(4):607-621. doi: 10.1158/1541-7786.MCR-21-0374.
There is a continued need to identify novel therapeutic targets to prevent the mortality associated with prostate cancer. In this context, mitochondrial Rho GTPase 2 (MIRO2) mRNA was upregulated in metastatic prostate cancer compared with localized tumors, and higher MIRO2 levels were correlated with poor patient survival. Using human cell lines that represent androgen-independent or -sensitive prostate cancer, we showed that MIRO2 depletion impaired cell growth, colony formation, and tumor growth in mice. Network analysis of MIRO2's binding partners identified metabolism and cellular responses to extracellular stimuli as top overrepresented pathways. The top hit on our screen, General Control Nonderepressible 1 (GCN1), was overexpressed in prostate cancer, and interacted with MIRO2 in prostate cancer cell lines and in primary prostate cancer cells. Functional analysis of MIRO2 mutations present in patients with prostate cancer led to the identification of MIRO2 159L, which increased GCN1 binding. Importantly, MIRO2 was necessary for efficient GCN1-mediated GCN2 kinase signaling and induction of the transcription factor activating transcription factor 4 (ATF4) levels. Further, MIRO2's effect on regulating prostate cancer cell growth was mediated by ATF4. Finally, levels of activated GCN2 and ATF4 were correlated with MIRO2 expression in prostate cancer xenografts. Both MIRO2 and activated GCN2 levels were higher in hypoxic areas of prostate cancer xenografts. Overall, we propose that targeting the MIRO2-GCN1 axis may be a valuable strategy to halt prostate cancer growth.
MIRO2/GCN1/GCN2 constitute a novel mitochondrial signaling pathway that controls androgen-independent and androgen-sensitive prostate cancer cell growth.
需要继续确定新的治疗靶点，以预防与前列腺癌相关的死亡率。在这种情况下，转移性前列腺癌中与局部肿瘤相比，线粒体 Rho GTPase 2（MIRO2）mRNA 上调，并且较高的 MIRO2 水平与患者预后不良相关。使用代表雄激素非依赖性或敏感性前列腺癌的人细胞系，我们表明 MIRO2 耗竭会损害细胞生长，集落形成和小鼠中的肿瘤生长。MIRO2 结合伙伴的网络分析表明，代谢和细胞对细胞外刺激的反应是最突出的途径。我们筛选的顶级命中是 General Control Nonderepressible 1（GCN1），它在前列腺癌中过表达，并且在前列腺癌细胞系和原发性前列腺癌细胞中与 MIRO2 相互作用。对存在于前列腺癌患者中的 MIRO2 突变的功能分析导致鉴定出 MIRO2 159L，其增加了 GCN1 结合。重要的是，MIRO2 对于有效 GCN1 介导的 GCN2 激酶信号传导和转录因子激活转录因子 4（ATF4）水平的诱导是必需的。此外，MIRO2 对调节前列腺癌细胞生长的作用是通过 ATF4 介导的。最后，在前列腺癌异种移植物中，激活的 GCN2 和 ATF4 的水平与 MIRO2 的表达相关。MIRO2 和激活的 GCN2 水平在前列腺癌异种移植物的缺氧区域中均较高。总体而言，我们提出靶向 MIRO2-GCN1 轴可能是阻止前列腺癌生长的有效策略。
MIRO2/GCN1/GCN2 构成了一种新的线粒体信号通路，可控制雄激素非依赖性和雄激素敏感性前列腺癌细胞的生长。
