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中华细胞与干细胞杂志(电子版)

中华细胞与干细胞杂志(电子版) ›› 2026, Vol. 16 ›› Issue (01) : 1 -12. doi: 10.3877/cma.j.issn.2095-1221.2026.01.001

论著

APR-246通过再激活突变型p53诱导膀胱癌细胞铁死亡与细胞周期阻滞
张弛1,2, 董宇豪2,3, 曹森明1,2, 王闯2,3, 黄燕2, 张旭1,2,†()   
  1. 1300071　天津，南开大学医学院
    2100039　北京，中国人民解放军总医院泌尿外科医学部
    3100853　北京，解放军医学院
  • 收稿日期:2025-10-22 出版日期:2026-02-01
  • 通信作者: 张旭

APR-246 induces ferroptosis and cell cycle arrest in bladder cancer cells through reactivation of mutant p53

Chi Zhang1,2, Yuhao Dong2,3, Senming Cao1,2, Chuang Wang2,3, Yan Huang2, Xu Zhang1,2,†()   

  1. 1School of Medicine, Nankai University, Tianjin 300071, China
    2Senior Department of Urology, Chinese PLA General Hospital, Beijing 100039, China
    3Medical School of PLA, Beijing 100853, China
  • Received:2025-10-22 Published:2026-02-01
  • Corresponding author: Xu Zhang
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引用本文：

张弛, 董宇豪, 曹森明, 王闯, 黄燕, 张旭. APR-246通过再激活突变型p53诱导膀胱癌细胞铁死亡与细胞周期阻滞[J/OL]. 中华细胞与干细胞杂志(电子版), 2026, 16(01): 1-12.

Chi Zhang, Yuhao Dong, Senming Cao, Chuang Wang, Yan Huang, Xu Zhang. APR-246 induces ferroptosis and cell cycle arrest in bladder cancer cells through reactivation of mutant p53[J/OL]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2026, 16(01): 1-12.

目的

探讨p53再激活小分子药物eprenetapopt （APR-246）在膀胱癌细胞中的抗肿瘤作用及其分子机制。

方法

采用多种人源及鼠源膀胱癌细胞系，检测APR-246对不同p53状态细胞的敏感性，并通过RNA干扰构建p53敲低模型以评估药物作用依赖性。在敲低实验中，细胞将转染shScramble空载体慢病毒命名为Scramble组，转染shp53慢病毒命名为shp53组。在过表达实验中，细胞转染pLKO NC空载体慢病毒命名为NC （对照）组和转染过表达p53R248S慢病毒命名为OEp53R248S。利用细胞活力测定、ROS染色及Western blot检测分析细胞死亡形式及相关蛋白表达，实验分组为细胞分为空白对照命名为DMSO组，20 μmol/L APR-246处理命名为APR-246处理组及20 μmol/L APR-246 + 5 mmol/L NAC同步处理命名为APR-246 + NAC；同时通过流式细胞术与小鼠皮下移植瘤模型验证其体内外生物学效应。两组间比较采用独立样本t检验；多组间比较采用单因素方差分析，多组间两两比较采用Dunnett's t检验。

结果

APR-246可诱导膀胱癌细胞死亡（EJ：IC50 =14.09 μmol/L；T24：IC50 = 13.56 μmol/L；UMUC3：IC50 = 15.14 μmol/ L；SW780：IC50 = 29.71 μmol/L；MB49：IC50 = 7.02 μmol/L；MBT2：IC50 = 1.119 μmol/L；P均< 0.05），且突变型p53细胞（EJ、T24、UMUC3、MBT2）比野生型p53细胞（SW780、MB49）对药物更敏感；敲低突变型p53后细胞对药物反应减弱（UMUC3：17.69 ± 0.21比24.16 ± 0.24；EJ：12.24 ± 0.17比19.61 ± 0.29；T24：11.39 ± 0.26比16.24 ± 0.35） （P均< 0.05）；过表达突变型p53后细胞对药物反应减弱[UMUC3:（18.93 ± 0.57比13.42 ± 0.45） μmol/L；EJ：（13.05 ± 0.32比8.21 ± 0.27） μmol/L；T24：（13.23 ± 0.46比9.21 ± 0.42） μmol/L） （P均< 0.05）]。APR-246诱导的细胞死亡主要依赖ROS介导的铁死亡与凋亡，APR-246处理导致SLC7A11和GPX4表达下调以及被剪切的PARP蛋白增多（P均< 0.05）。另外，APR-246在p53错义突变型膀胱癌细胞中诱导p21上调及细胞周期阻滞[G0/G1期细胞（36.44 ± 0.65）%比（53.32 ± 0.83）%]（P均< 0.05）。动物实验进一步证实APR-246可抑制肿瘤生长（P < 0.05）。

结论

APR-246通过再激活突变型p53并诱导ROS-依赖的铁死亡和细胞周期阻滞发挥抗肿瘤作用，为膀胱癌的精准治疗提供新的分子靶点和实验依据。

关键词: 膀胱癌, p53, APR-246, 铁死亡, 细胞周期阻滞
Objective

To investigate the antitumor effects and underlying molecular mechanisms of the p53 reactivator APR-246 in bladder cancer cells.

Methods

Human and murine bladder cancer cell lines with different p53 statuses were treated with APR-246 to assess drug sensitivity. p53-knockdown mutant cell models were established to evaluate the dependency of APR-246 on p53. For knockdown experiments, cells transduced with lentiviral shScramble were named as Scramble group, whereas cells transduced with shp53 were named as shp53 group. For overexpression experiments, cells transduced with empty pLKO-NC lentivirus were served as the control (NC) , and cells transduced with lentivirus overexpressing p53R248S were named as the OE-p53R248S group. Cell viability assay, ROS staining, and Western blot were performed to analyze cell death patterns and related protein expression. Cells were treated with DMSO (control) , 20 μmol/L APR-246, or 20 μmol/L APR-246 combined with 5 mmol/L NAC. Flow cytometry and a subcutaneous xenograft model in C3H mice were used to validate the biological effects in vitro and in vivo. Differences between two groups were assessed using the independent-samples t test. Comparisons among multiple groups were conducted by one-way analysis of variance (ANOVA) , followed by Dunnett's t test for multiple comparisons between each treatment group and the control group.

Results

APR-246 significantly induced cell death in bladder cancer cell lines (EJ: IC50 = 14.09 μmol/L; T24: IC50 = 13.56 μmol/L; UMUC3: IC50 = 15.14 μmol/L; SW780: IC50 = 29.71 μmol/L; MB49: IC50 = 7.02 μmol/L; MBT2: IC50 = 1.12 μmol/L; all P < 0.05) , whereas mutant p53 cells exhibited greater sensitivity to the compound. Knockdown of p53 attenuated cellular responses to APR-246 (UMUC3: 17.69 ± 0.21 vs 24.16 ± 0.24; EJ: 12.24 ± 0.17 vs 19.61 ± 0.29; T24:11.39 ± 0.26 vs 16.24 ± 0.35; all P < 0.05) .Overexpression of mutant p53 reduced drug responsiveness [UMUC3: (18.93 ± 0.57) vs (13.42 ± 0.45) μmol/L; EJ: (13.05 ± 0.32) vs (8.21 ± 0.27) μmol/L; T24: (13.23 ± 0.46) vs (9.21 ± 0.42) μmol/L; all P < 0.05]. Cell death induced by APR-246 was primarily mediated through ROS-dependent ferroptosis and apoptosis. Treatment with APR-246 could downregulate the expression of SLC7A11 and GPX4 (P < 0.05) and increased the expression level of cleaved PARP (P < 0.05) . Furthermore, in bladder cancer cells harboring p53 missense mutations, APR-246 upregulated the expression of p21 and induced cell cycle arrest at the G0/G1 phase [ (37.44 ± 0.65) % vs (53.32 ± 0.83) %; P < 0.05]. In vivo studies further confirmed that APR-246 markedly inhibited tumor growth (P < 0.05) .

Conclusion

APR-246 exerts potent antitumor activity in bladder cancer by reactivating mutant p53 and inducing ROS-dependent ferroptosis and cell cycle arrest, providing a promising molecular target and experimental basis for precision therapy of bladder cancer.

Key words: Bladder cancer, p53, APR-246, Ferroptosis, Cell cycle arrest
表1 引物序列信息
基因 序列（5'→3'） 预期扩增产物长度（bp）
p53 上游TGAAGCTCCCAGAATGCCAG 125
  下游GCTGCCCTGGTAGGTTTTCT  
p21/CDKN1A 上游TGTCCGTCAGAACCCATGC 139
  下游AAAGTCGAAGTTCCATCGCTC  
GAPDH （内参） 上游ATTCCATGGCACCGTCAAGGCTGA 156
  下游TTCTCCATGGTGGTGAAGACGCCA  
图1 膀胱癌患者p53基因突变概况注：a图为检索公共数据库（cBioPortal for Cancer Genomics）的4 796名膀胱癌患者p53基因突变比例；b图为所有突变患者中不同突变类型比例，部分患者同时携带不止1种p53基因突变
图2 APR-246诱导膀胱癌细胞死亡的IC50
图3 APR-246诱导膀胱癌细胞死亡的作用依赖于p53注：a图为Western blot实验检测UMUC3、EJ、T24细胞中p53的敲低效率；b图为Western blot实验检测UMUC3、EJ、T24细胞中外源添加突变型p53R248S的蛋白表达；c图为在UMUC3、EJ、T24细胞中敲低p53后APR-246的IC50的对比，3种细胞均显示敲低突变型p53后，APR-246的IC50升高；d图为在UMUC3、EJ、T24细胞中过表达突变型p53R248S后APR-246的IC50的对比，3种细胞均显示敲低突变型p53后，APR-246的IC50降低
表2 敲低p53后UMUC3、EJ和T24细胞内p53 mRNA及蛋白相对表达（ ± s，n = 3）
分组 UMUC3 EJ T24
p53mRNA相对表达量 p53蛋白相对表达量 p53mRNA相对表达量 p53蛋白相对表达量 p53 mRNA相对表达量 p53蛋白相对表达量
Scramble 1.00 ± 0.02 1.01 ± 0.01 1.01 ± 0.16 1.00 ± 0.03 1.02 ± 0.03 1.04 ± 0.12
shp53 0.10 ± 0.01 0.24 ± 0.04 0.13 ± 0.02 0.29 ± 0.17 0.12 ± 0.04 0.21 ± 0.05
t值 78.353 43.364 57.278 39.462 58.487 47.256
P值 0.039 0.012 0.007 0.018 0.025 0.021
表3 过表达Mut p53后UMUC3、EJ和T24细胞内p53 mRNA及蛋白相对表达（ ± s，n = 3）
分组 UMUC3 EJ T24
p53 mRNA相对表达量 p53蛋白相对表达量 p53 mRNA相对表达量 p53蛋白相对表达量 p53 mRNA相对表达量 p53蛋白相对表达量
NC 1.01 ± 0.08 1.04 ± 0.03 1.03 ± 0.10 1.12 ± 0.08 1.05 ± 0.09 1.14 ± 0.18
OEp53R248S 10.10 ± 0.59 11.24 ± 0.94 8.37 ± 0.42 8.29 ± 0.58 6.14 ± 0.41 6.35 ± 0.34
t值 85.458 56.392 78.251 63.478 59.259 45.973
P值 0.013 0.022 0.009 0.015 0.006 0.017
图4 细胞死亡挽救实验细胞活力分析结果注：与DMSO组比较，***P < 0.001；ns为差异无统计学意义；n = 3
图5 荧光显微镜下观察UMUC3细胞ROS水平变化（×200）注：明场图片和荧光通道的合并图（叠加）和单纯ROS荧光通道，标尺为200 μm
图6 Western blot检测结果及细胞内还原态与氧化态脂质荧光图（×200）注：a图为Western blot实验检测APR-246处理后UMUC3、EJ细胞中铁死亡标志物SLC7A11和GPX4表达水平的变化；b图为Western blot实验检测APR-246处理后UMUC3、EJ细胞中凋亡标志物PARP蛋白剪切水平的变化；c图为用BDPY 581/591 C11荧光探针检测APR-246处理后UMUC3细胞内脂质过氧化的效果变化，绿色荧光代表氧化态脂质，橘红色荧光代表还原态脂质，标尺为200 μm
表4 UMUC3和EJ细胞经APR-246处理后SLC7A11、GPX4水平（ ± s）
分组 实验次数 UMUC3 EJ
SLC7A11蛋白相对表达量 GPX4蛋白相对表达量 SLC7A11蛋白相对表达量 GPX4蛋白相对表达量
DMSO 3 1.06 ± 0.13 1.05 ± 0.08 1.03 ± 0.10 1.09 ± 0.06
APR-246 3 0.07 ± 0.01 0.18 ± 0.02 0.21 ± 0.03 0.09 ± 0.29
t值   13.676 12.561 9.173 15.228
P值   0.023 0.015 0.041 0.032
表5 UMUC3和EJ细胞经APR-246处理后PARP剪切水平（ ± s）
分组 实验次数 UMUC3 EJ
PARP全长蛋白相对表达量 PARP剪切蛋白相对表达量 PARP全长蛋白相对表达量 PARP剪切蛋白相对表达量
DMSO 3 0.98 ± 0.11 1.06 ± 0.09 1.05 ± 0.13 1.03 ± 0.05
APR-246 3 2.83 ± 0.35 7.46 ± 0.74 3.06 ± 0.49 9.35 ± 0.68
APR-246+NAC 3 1.15 ± 0.13 3.85 ± 0.56 2.21 ± 0.35 3.09 ± 0.17
t值   19.452 28.368 14.565 35.432
P值   0.029 0.012 0.014 0.025
图7 Western blot实验检测DMSO组和APR-246处理组UMUC3、EJ细胞中p21的蛋白表达水平注：与DMSO组比较，***P < 0.001
图8 荧光显微镜下观察UMUC3细胞形态和染色体形态变化（×200）注：显微镜下观察DMSO组和APR-246处理组UMUC3、EJ细胞形态（a图）和用碘化丙啶（PI）对死亡细胞的核染色体进行染色的荧光图片（b图），标尺为200 μm
图9 流式术分析DMSO组和APR-246处理组UMUC3细胞的细胞周期比例
表6 UMUC3和EJ细胞经APR-246处理后p21水平上调（ ± s）
分组 实验次数 UMUC3 EJ
p21 mRNA相对表达量 p21蛋白相对表达量 p21 mRNA相对表达量 p21蛋白相对表达量
DMSO 3 1.01 ± 0.11 1.03 ± 0.04 1.01 ± 0.20 0.99 ± 0.05
APR-246 3 1.89 ± 0.26 1.74 ± 0.15 1.93 ± 0.22 1.79 ± 0.29
t值   52.617 36.252 49.133 28.501
P值   0.012 0.008 0.027 0.019
表7 UMUC3细胞经APR-246处理后的各细胞周期比例（ ± s，%）
分组 实验次数 G0/G1期细胞比例 S期细胞比例 G2/M期细胞比例
DMSO 3 36.44 ± 0.65 48.18 ± 0.64 15.51 ± 0.57
APR-246 3 53.32 ± 0.83 38.25 ± 0.47 8.43 ± 0.29
t值   27.886 9.362 10.613
P值   0.041 0.017 0.021
图10 APR-246在小鼠体内抑制膀胱癌肿瘤生长注：a图为正常视野下观察小鼠皮下成瘤；b、c图分别为不同处理组小鼠皮下成瘤的质量及体积变化曲线。***P < 0.001
表8 APR-246治疗后C3H小鼠皮下成瘤的质量和体积（ ± s）
分组 小鼠数量（只） 皮下瘤质量（mg） 皮下瘤体积（mm3）
DMSO 5 1093.10 ± 325.13 999.23 ± 301.01
APR-246 5 240.82 ± 155.37 363.78 ± 120.14
t值   4.564 4.229
P值   0.027 0.021
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