Genomics Research Center, Academia Sinica, Taipei, Taiwan.
Translational Research Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
Cancer Res. 2019 Sep 15;79(18):4754-4766. doi: 10.1158/0008-5472.CAN-18-4080. Epub 2019 Jul 29.
Cancer metabolic reprogramming promotes tumorigenesis and metastasis; however, the underlying molecular mechanisms are still being uncovered. In this study, we show that the glycolytic enzyme aldolase A (ALDOA) is a key enzyme involved in lung cancer metabolic reprogramming and metastasis. Overexpression of ALDOA increased migration and invasion of lung cancer cell lines and formation of metastatic lung cancer foci . ALDOA promoted metastasis independent of its enzymatic activity. Immunoprecipitation and proteomic analyses revealed γ-actin binds to ALDOA; blocking this interaction using specific peptides decreased metastasis both and . Screening of clinically available drugs based on the crystal structure of ALDOA identified raltegravir, an antiretroviral agent that targets HIV integrase, as a pharmacologic inhibitor of ALDOA-γ-actin binding that produced antimetastatic and survival benefits in a xenograft model with no significant toxicity. In summary, ALDOA promotes lung cancer metastasis by interacting with γ-actin. Targeting this interaction provides a new therapeutic strategy to treat lung cancer metastasis. SIGNIFICANCE: This study demonstrates the role of aldolase A and its interaction with γ-actin in the metastasis of non-small lung cancer and that blocking this interaction could be an effective cancer treatment.
癌症代谢重编程促进肿瘤发生和转移；然而，其潜在的分子机制仍在探索中。在这项研究中，我们表明，糖酵解酶醛缩酶 A（ALDOA）是参与肺癌代谢重编程和转移的关键酶。ALDOA 的过表达增加了肺癌细胞系的迁移和侵袭 ，并形成转移性肺癌病灶 。ALDOA 促进转移不依赖于其酶活性。免疫沉淀和蛋白质组学分析表明 γ-肌动蛋白与 ALDOA 结合；使用特异性肽阻断这种相互作用可减少转移 。根据 ALDOA 的晶体结构筛选临床可用药物，发现 raltegravir（一种针对 HIV 整合酶的抗逆转录病毒药物）是 ALDOA-γ-肌动蛋白结合的药理学抑制剂，在没有明显毒性的异种移植模型中产生了抗转移和生存益处。总之，ALDOA 通过与 γ-肌动蛋白相互作用促进肺癌转移。靶向这种相互作用为治疗肺癌转移提供了一种新的治疗策略。意义：本研究表明醛缩酶 A 及其与 γ-肌动蛋白的相互作用在非小细胞肺癌转移中的作用，阻断这种相互作用可能是一种有效的癌症治疗方法。
