Inhibition of PP2A by LB100 sensitizes bladder cancer cells to chemotherapy by inducing p21 degradation.
Inhibition of PP2A by LB100 sensitizes bladder cancer cells to chemotherapy by inducing p21 degradation.
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LB100 对 PP2A 的抑制通过诱导 p21 降解使膀胱癌细胞对化疗敏感。
DOI：
10.1007/s13402-022-00710-8
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发表时间：
2022-09
期刊：
影响因子：
--
通讯作者：
Liu Yang
中科院分区：
文献类型：
--
作者：
Gao Song;Shan Liping;Zhang Mo;Wang Yan;Zhan Xi;Yin Yalei;Jiang Zhonghao;Tao Xinyi;Li xinyu;Ye Mingliang;Liu Yang
膀胱癌(BLCA)是最常见的尿路恶性肿瘤，对化疗疗效差。蛋白磷酸酶2A(PP2A)是一种丝氨酸/苏氨酸磷酸酶，参与多种细胞调控过程，包括细胞凋亡和DNA损伤反应(DDR)。LB100是一种PP2A的小分子抑制剂，已被证明在多种类型的癌症中起到化学敏感剂的作用。然而，LB100在BLCA中的抗肿瘤作用和作用机制尚不清楚。方法通过体内外实验，评价LB100单独或与吉西他滨合用的抗肿瘤作用。利用质谱仪(MS)对PP2A下游底物进行鉴定，探讨LB100诱导DNA损伤和细胞凋亡的机制。此外，我们通过长期药物暴露建立了耐药的BLCA细胞系(RT-112-R)，并检测了LB100对BLCA细胞株和异种小鼠模型的遗传毒性的增强作用。结果我们发现LB100在体内外都可以通过诱导DNA损伤和凋亡来诱导BLCA细胞的抗肿瘤反应。此外，我们还发现PP2A可能通过去磷酸化p-p21-ser130来稳定p21。LB100抑制PP2A使p-p21-Ser130水平升高，随后导致p21水平降低，并呈剂量依赖性。此外，我们还发现LB100处理取消了G1/S细胞周期检查点，导致γH2AX的磷酸化增加。此外，LB100在体内外通过诱导DNA损伤和凋亡增强了对化疗耐药的BLCA细胞的遗传毒性。结论PP2A可能通过调节p21的稳定性而成为治疗BLCA的潜在靶点。
PurposeBladder carcinoma (BLCA) is the most common urinary tract malignancy and exhibits a poor response to chemotherapy. Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase involved in a wide variety of regulatory cellular processes, including apoptosis and the DNA-damage response (DDR). LB100, a small molecule inhibitor of PP2A, has been shown to act as a chemo-sensitizer in multiple types of cancer. However, the anti-tumor effect and mode of action of LB100 in BLCA have yet to be identified.MethodsIn vitro and in vivo experiments were performed to assess the anti-tumor effect of LB100 alone or in combination with gemcitabine. Mass spectrometry (MS)-based phosphoproteomics analysis was used to identify the downstream substrates of PP2A and to explore the mechanism underlying LB100-induced DNA damage and apoptosis. In addition, we established a chemo-resistant BLCA cell line (RT-112-R) by prolonged drug exposure and determined the effect of LB100 in enhancing genotoxicity in BLCA cell lines and xenograft mouse models.ResultsWe found that LB100 is sufficient to induce an anti-tumor response in BLCA cells by inducing DNA damage and apoptosis both in vitro and in vivo.Furthermore, we found that PP2A potentially dephosphorylates p-p21-ser130 to stabilize p21. Inhibition of PP2A by LB100 increased the level of p-p21-ser130, subsequently leading to a reduction in p21 level in a dose-dependent manner. In addition, we found that treatment of LB100 abrogated the G1/S cell cycle checkpoint, resulting in increased phosphorylation of γH2AX in BLCA cells. Moreover, LB100 enhanced genotoxicity in chemo-resistant BLCA cells by inducing DNA damage and apoptosis in vitro and in vivo.ConclusionOur findings indicate that PP2A may serve as a potential therapeutic target in BLCA through regulating p21 stability.
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