Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia, USA.
Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine and Health Science, Washington, District of Columbia, USA.
Cancer Med. 2023 Jan;12(1):488-499. doi: 10.1002/cam4.4911. Epub 2022 Jun 6.
The AMP-activated protein kinase (AMPK) is a central regulator of energy homeostasis, with deregulation leading to cancer and other diseases. However, how this pathway is dysregulated in cancer has not been well clarified.
Using a tandem affinity purification/mass-spec technique and biochemical analyses, we identified tumor protein D52 (TPD52) as an AMPKα-interacting molecule. To explore the biological effects of TPD52 in cancers, we conducted biochemical and metabolic assays in vitro and in vivo with cancer cells and TPD52 transgenic mice. Finally, we assessed the clinical significance of TPD52 expression in breast cancer patients using bioinformatics techniques.
TPD52, initially identified to be overexpressed in many human cancers, was found to form a stable complex with AMPK in cancer cells. TPD52 directly interacts with AMPKα and inhibits AMPKα kinase activity in vitro and in vivo. In TPD52 transgenic mice, overexpression of TPD52 leads to AMPK inhibition and multiple metabolic defects. Clinically, high TPD52 expression predicts poor survival of breast cancer patients.
The findings revealed that TPD52 is a novel regulator of energy stress-induced AMPK activation and cell metabolism. These results shed new light on AMPK regulation and understanding of the etiology of cancers with TPD52 overexpression.
AMP 激活的蛋白激酶 (AMPK) 是能量平衡的核心调节剂，其失调会导致癌症和其他疾病。然而，这条途径在癌症中是如何失调的还没有得到很好的阐明。
我们使用串联亲和纯化/质谱技术和生化分析，鉴定肿瘤蛋白 D52（TPD52）为 AMPKα 的相互作用分子。为了探索 TPD52 在癌症中的生物学效应，我们在体外和体内使用癌细胞和 TPD52 转基因小鼠进行了生化和代谢测定。最后，我们使用生物信息学技术评估了 TPD52 表达在乳腺癌患者中的临床意义。
TPD52 最初在许多人类癌症中被发现过度表达，它在癌细胞中与 AMPK 形成稳定的复合物。TPD52 直接与 AMPKα 相互作用，并在体外和体内抑制 AMPKα 激酶活性。在 TPD52 转基因小鼠中，TPD52 的过表达导致 AMPK 抑制和多种代谢缺陷。临床上，高 TPD52 表达预示着乳腺癌患者的生存不良。
这些发现表明，TPD52 是能量应激诱导的 AMPK 激活和细胞代谢的新型调节剂。这些结果为 AMPK 调节和理解 TPD52 过表达的癌症病因提供了新的视角。
