Roh Jongtae, Ahn Inho, Choi Jong-Ryoo, Ko Sung-Kyun
Chemical Biology Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju 28116, South Korea; Department of Biomolecular Science, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon 34141, South Korea.
J&C Sciences, Migun TW2 410, 187 techno 2-ro, Yusung, Daejeon, South Korea.
Transl Oncol. 2025 Jul 23;60:102478. doi: 10.1016/j.tranon.2025.102478.
Cancer cells exhibit abnormal proliferation and dysregulated cell cycle checkpoints. Therefore, discovering cell cycle inhibitors is a promising strategy for cancer treatment. The pyrroline-5-carboxylate reductase 1 (PYCR1) is a key enzyme that controls proline metabolism by regulating the conversion of pyrroline-5-carboxylate to proline. PYCR1 is highly expressed in various cancers, including colon cancer. In this study, we discovered a novel role of 9-deazaadenosine (9-DAA) as a cell cycle inhibitor and demonstrated that this compound directly binds to PYCR1. Our results suggest that the inhibitory effects of 9-DAA are due to nicotinamide adenine dinucleotide. We further demonstrated that PYCR1 was elevated under hypoxia and in 3D spheroids in colon cancer and that 9-DAA effectively inhibited cancer progression under cancer-mimicking conditions and in vivo.
癌细胞表现出异常增殖和细胞周期检查点失调。因此，发现细胞周期抑制剂是一种很有前景的癌症治疗策略。吡咯啉-5-羧酸还原酶1（PYCR1）是一种关键酶，通过调节吡咯啉-5-羧酸向脯氨酸的转化来控制脯氨酸代谢。PYCR1在包括结肠癌在内的各种癌症中高度表达。在本研究中，我们发现了9-脱氮腺苷（9-DAA）作为一种细胞周期抑制剂的新作用，并证明该化合物直接与PYCR1结合。我们的结果表明，9-DAA的抑制作用归因于烟酰胺腺嘌呤二核苷酸。我们进一步证明，在结肠癌的缺氧条件下和三维球体中，PYCR1水平升高，并且9-DAA在模拟癌症的条件下和体内均能有效抑制癌症进展。
