Department of Oral Biology and Diagnostic Sciences, Georgia Cancer Center, Augusta University, Augusta, GA, 30912, USA.
Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, 201 Dowman Dr, Atlanta, GA, 30322, USA.
J Exp Clin Cancer Res. 2022 Jan 29;41(1):43. doi: 10.1186/s13046-022-02274-9.
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.
靶向线粒体癌蛋白为有效癌症治疗的发展提出了新概念。ATAD3A 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，它在癌症中的影响和潜在的调节机制仍不清楚。
我们使用头颈部鳞状细胞癌 (HNSCC) 作为研究平台，通过慢病毒 shRNA 和 CRISPR/Cas9 实现基因缺失。通过 RNA 测序、磷酸激酶谱分析、Western blot、RT-qPCR、免疫组织化学和免疫沉淀检测分子改变。通过 MTT、集落形成、软琼脂和 3D 培养评估癌细胞生长。在荷瘤 NSG 小鼠的原位舌肿瘤中评估治疗效果。
ATAD3A 在 HNSCC 组织和细胞系中高度表达。ATAD3A 表达缺失抑制 HNSCC 细胞生长，并在荷瘤原位小鼠中引发肿瘤消退，而 ATAD3A 表达增加则产生相反的效果。从机制角度来看，由于 ATP 结合缺陷，ATAD3A 的 Walker A 缺失突变体（K358）的过表达诱导的肿瘤抑制产生了强大的显性负效应。此外，在存在 VDAC1 的情况下，ATAD3A 与 HNSCC 细胞线粒体中的 ERK1/2 结合，这种相互作用对于激活线粒体 ERK1/2 信号通路至关重要。最重要的是，ATAD3A-ERK1/2 信号轴以 RAS 非依赖性方式驱动 HNSCC 发展，因此，当 ATAD3A 敲除与 RAS 抑制剂联合治疗时，肿瘤抑制作用更有效。
这些发现强调了 ATAD3A 在调节线粒体 ERK1/2 激活以促进 HNSCC 发展中的新功能。联合靶向 ATAD3A 和 RAS 信号可能增强 HNSCC 治疗的抗癌活性。
