On July 12, the team of Lingyi Kong/Yuanzheng Xia/Kaibo Wang published their latest research results titled “Overcoming Cancer Persister Cells by Stabilizing the ATF4 Promoter G-quadruplex” in Advanced Science, a leading journal in the field. quadruplex”. Dr. Xiao Chengmei (PhD student, class of 2021), Dr. Li Yipu (PhD student, class of 2022), and Associate Professor Liu Yushang (PhD student, class of 2022) are the co-first authors of this article, while Prof. Kong Lingyi, Associate Prof. Xia Yuanzheng and Wang Kaibo are the co-corresponding authors, and the China Pharmaceutical University (CPU) is the sole correspondent of this article.
In cancer therapy, persistent cells (PS) have been recognized as important contributors to the development of drug-resistant malignancies and ultimately lead to unpredictable cancer progression. In primary solid tumors where glutamine is often observed to be “depleted”, the team found that imposed glutamine restriction induced PS production, which enhanced treatment resistance by activating the GCN2-ATF4-ASCT2 axis initiated by the integrative stress response, a phenomenon centered on stress-induced ATF4 translational reprogramming. Thus, in the context of glutamine nutrient-limited therapy, ATF4 inhibition would be a potential therapeutic strategy to hamper the persistent phenotype of cancer. However, screening small molecule inhibitors directly targeting ATF4 is considered to be a great challenge due to the specific structure of ATF4 protein. In view of the “non-druggable” nature of ATF4 protein and the current good results of G-quadruplex-targeted drugs in clinical trials, the team clarified that the ATF4 promoter region can form a G-quadruplex structure (ATF4-G4), and screened and determined that the active ingredient of the traditional Chinese medicine (TCM), Coptisine (COP), is a molecule that binds to the ATF4 promoter region. COP) is a potent stabilizer that interacts with ATF4-G4 and stabilizes its special structure, and the high-resolution structure of the COP-ATF4-G4 complex was resolved for the first time. In addition, the unique metabolic profile of safranine was observed in glutamine-restricted therapy, and the transcriptional activation of the transcription factor TFAP2A in relation to ATF4 was discovered by a comprehensive screen.
These seminal findings emphasize that targeting ATF4 is the key to reversing the phenomenon of tumor-adaptive survival induced by glutamine-restricted therapy, reveal the structural features of ATF4-G4, and reveal that the active ingredient of traditional Chinese medicine, Huanglianine, interferes with and breaks the resistance of cancer persistent cells to treatment, filling the current gaps in the field of glutamine-restricted therapy and providing a new idea for the in-depth research and rational application of the active ingredients of traditional Chinese medicine It also provides new ideas for the in-depth research and rational application of active ingredients in traditional Chinese medicine.
This research work was supported by the National Natural Science Excellent Youth Science Foundation of China and the Upper Level Fund (82322065, 81973524); the Natural Science Foundation of Jiangsu Province (BK20221039) and other programs.
Article link: https://onlinelibrary.wiley.com/doi/10.1002/advs.202401748
