阿里斯洛胆胆酸酯 - 散发的p53通过抑制铁毒性促进肝癌细胞的生长
Aristolochic acids-hijacked p53 promotes liver cancer cell growth by inhibiting ferroptosis
影响因子:8.40000
分区:医学2区 / 药学1区 化学：综合2区
发表日期:2025 Jan
作者:
Chun-Yu Hou, Yu-Hong Suo, Pan Lv, Hong-Feng Yuan, Li-Na Zhao, Yu-Fei Wang, Hui-Hui Zhang, Jiao Sun, Lin-Lin Sun, Wei Lu, Ning-Ning Zhang, Guang Yang, Xiao-Dong Zhang
摘要
aristolochic酸（AAS）已被确定为肝细胞癌（HCC）的重要危险因素。铁凋亡是肿瘤发育中涉及的一种受调节的细胞死亡。在这项研究中，我们研究了AAS增强HCC生长的分子机制。通过进行生物信息学和RNA-seq分析，我们发现AAS与铁凋亡密切相关。通过生物信息学分析和SPR分析验证了p53和AAS之间的物理相互作用，并与包含Pro92，arg174，asp207，phe212和His214的结合口袋位点的SPR分析验证。基于与AAS相互作用的结合袋，我们设计了一个突变体并进行了RNA-Seq分析。有趣的是，我们发现结合口袋负责铁铁，GADD45A，NRF2和SLC7A11。在功能上，相互作用扰乱了p53与GADD45A或NRF2的启动子的结合，从而减弱了p53在增强GADD45A并抑制NRF2中的作用；突变体没有表现出相同的效果。因此，该事件下调了GADD45A和上调的NRF2，最终抑制了铁毒性，表明AAS劫持了p53以下调GADD45A并在HEPG2细胞中上调NRF2。因此，AAS治疗导致通过p53/gadd45a/nrf2/slc7a11轴抑制螺旋病，从而导致肿瘤生长的增强。总之，AAS-HIJACK的P53通过GADD45A/NRF2/SLC7A11轴限制了铁铁作用，以增强肿瘤的生长。我们的发现提供了一种基本机制，AAS通过该机制增强了HCC和对肝癌中p53的新见解。在治疗上，癌基因NRF2是肝癌的有希望的靶标。
Abstract
Aristolochic acids (AAs) have been identified as a significant risk factor for hepatocellular carcinoma (HCC). Ferroptosis is a type of regulated cell death involved in the tumor development. In this study, we investigated the molecular mechanisms by which AAs enhanced the growth of HCC. By conducting bioinformatics and RNA-Seq analyses, we found that AAs were closely correlated with ferroptosis. The physical interaction between p53 and AAs in HepG2 cells was validated by bioinformatics analysis and SPR assays with the binding pocket sites containing Pro92, Arg174, Asp207, Phe212, and His214 of p53. Based on the binding pocket that interacts with AAs, we designed a mutant and performed RNA-Seq profiling. Interestingly, we found that the binding pocket was responsible for ferroptosis, GADD45A, NRF2, and SLC7A11. Functionally, the interaction disturbed the binding of p53 to the promoter of GADD45A or NRF2, attenuating the role of p53 in enhancing GADD45A and suppressing NRF2; the mutant did not exhibit the same effects. Consequently, this event down-regulated GADD45A and up-regulated NRF2, ultimately inhibiting ferroptosis, suggesting that AAs hijacked p53 to down-regulate GADD45A and up-regulate NRF2 in HepG2 cells. Thus, AAs treatment resulted in the inhibition of ferroptosis via the p53/GADD45A/NRF2/SLC7A11 axis, which led to the enhancement of tumor growth. In conclusion, AAs-hijacked p53 restrains ferroptosis through the GADD45A/NRF2/SLC7A11 axis to enhance tumor growth. Our findings provide an underlying mechanism by which AAs enhance HCC and new insights into p53 in liver cancer. Therapeutically, the oncogene NRF2 is a promising target for liver cancer.