ATAD3A mediates activation of RAS-independent mitochondrial ERK1/2 signaling, favoring head and neck cancer development.
ATAD3A mediates activation of RAS-independent mitochondrial ERK1/2 signaling, favoring head and neck cancer development.
复制标题
ATAD 3A介导RAS非依赖性线粒体ERK 1/2信号转导的激活，有利于头颈癌的发展。
DOI：
10.1186/s13046-022-02274-9
复制
发表时间：
2022-01-29
期刊：
影响因子：
--
通讯作者：
Teng Y
中科院分区：
文献类型：
--
作者：
Lang L;Loveless R;Dou J;Lam T;Chen A;Wang F;Sun L;Juarez J;Qin ZS;Saba NF;Shay C;Teng Y
靶向线粒体癌蛋白在有效的癌症治疗的发展中提出了一个新的概念。ATAD 3A是一种核编码的线粒体酶，有助于线粒体动力学、胆固醇代谢和信号转导。然而，其在癌症中的影响和潜在的调节机制仍然不明确。我们使用头颈部鳞状细胞癌（HNSCC）作为研究平台，并通过慢病毒shRNA和CRISPR/Cas9实现基因缺失。通过RNA测序、磷酸激酶分析、蛋白质印迹、RT-qPCR、免疫组织化学和免疫沉淀检查分子改变。通过MTT、集落形成、软琼脂和三维培养评估癌细胞生长。在原位舌肿瘤NSG小鼠中评价肿瘤发展的治疗功效。ATAD 3A在HNSCC组织和细胞系中高度表达。ATAD 3A表达的缺失抑制原位荷瘤小鼠中的HNSCC细胞生长和上皮性肿瘤消退，而ATAD 3A表达的获得产生相反的效果。从机制的角度来看，ATAD 3A（K358）的步行者A死亡突变体过表达诱导的肿瘤抑制由于ATP结合缺陷而产生有效的显性负效应。此外，在VDAC 1存在下，ATAD 3A与HNSCC细胞线粒体中的ERK 1/2结合，并且这种相互作用对于线粒体ERK 1/2信号传导的激活是必需的。最重要的是，ATAD 3A-ERK 1/2信号传导轴以RAS非依赖性方式驱动HNSCC发展，因此，当ATAD 3A敲除与RAS抑制剂治疗组合时，可更有效地实现肿瘤抑制。这些发现强调了ATAD 3A在调节线粒体ERK 1/2激活中的新功能，该功能有利于HNSCC的发展。ATAD 3A和RAS信号传导的组合靶向可增强HNSCC治疗剂的抗癌活性。在线版本包含补充材料，可通过10.1186/s13046-022-02274-9获得。
Targeting mitochondrial oncoproteins presents a new concept in the development of effective cancer therapeutics. ATAD3A is a nuclear-encoded mitochondrial enzyme contributing to mitochondrial dynamics, cholesterol metabolism, and signal transduction. However, its impact and underlying regulatory mechanisms in cancers remain ill-defined. We used head and neck squamous cell carcinoma (HNSCC) as a research platform and achieved gene depletion by lentiviral shRNA and CRISPR/Cas9. Molecular alterations were examined by RNA-sequencing, phospho-kinase profiling, Western blotting, RT-qPCR, immunohistochemistry, and immunoprecipitation. Cancer cell growth was assessed by MTT, colony formation, soft agar, and 3D cultures. The therapeutic efficacy in tumor development was evaluated in orthotopic tongue tumor NSG mice. ATAD3A is highly expressed in HNSCC tissues and cell lines. Loss of ATAD3A expression suppresses HNSCC cell growth and elicits tumor regression in orthotopic tumor-bearing mice, whereas gain of ATAD3A expression produces the opposite effects. From a mechanistic perspective, the tumor suppression induced by the overexpression of the Walker A dead mutant of ATAD3A (K358) produces a potent dominant-negative effect due to defective ATP-binding. Moreover, ATAD3A binds to ERK1/2 in the mitochondria of HNSCC cells in the presence of VDAC1, and this interaction is essential for the activation of mitochondrial ERK1/2 signaling. Most importantly, the ATAD3A-ERK1/2 signaling axis drives HNSCC development in a RAS-independent fashion and, thus, tumor suppression is more effectively achieved when ATAD3A knockout is combined with RAS inhibitor treatment. These findings highlight the novel function of ATAD3A in regulating mitochondrial ERK1/2 activation that favors HNSCC development. Combined targeting of ATAD3A and RAS signaling may potentiate anticancer activity for HNSCC therapeutics. The online version contains supplementary material available at 10.1186/s13046-022-02274-9.
登录
查看更多内容
影响因子：
3.7
作者：
Galli S;Jahn O;Hitt R;Hesse D;Opitz L;Plessmann U;Urlaub H;Poderoso JJ;Jares-Erijman EA;Jovin TM
通讯作者：
Jovin TM
影响因子：
5.6
作者：
Lang L;Loveless R;Teng Y
通讯作者：
Teng Y
影响因子：
--
作者：
Davis JE;Xie X;Guo J;Huang W;Chu WM;Huang S;Teng Y;Wu G
通讯作者：
Wu G
影响因子：
4
作者：
Camara AKS;Zhou Y;Wen PC;Tajkhorshid E;Kwok WM
通讯作者：
Kwok WM
影响因子：
5.3
作者：
Gilquin, Benoit;Taillebourg, Emmanuel;Baudier, Jacques
通讯作者：
Baudier, Jacques