Wang Kai-Hung, Chang Yu-Hsun, Ding Dah-Ching
Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien, 970, Taiwan.
Department of Pediatrics, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien, 970, Taiwan.
Sci Rep. 2025 Jul 1;15(1):21533. doi: 10.1038/s41598-025-08686-9.
Simvastatin, a 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitor, was used in cardiovascular diseases and could decrease low-density lipoprotein cholesterol, and may have a repurposed role in cancer therapy. However, the effects of simvastatin on endometrial cancer remain controversial. We aimed to elucidate the role and mechanisms of simvastatin in regulating previously identified endometrial cancer-associated mesenchymal stem cells (EmCaMSCs)-mediated immunosuppressive effects and anti-tumor progression. Coculture of EmCaMSCs and peripheral blood mononuclear cells (PBMC) was used to assay the population of CD8 + T cells, natural killer (NK) cells, and cytotoxicity of NK cells. The mechanisms were elucidated by applying recombinant proteins and inhibitors of candidate proteins, transforming growth factor-beta 2 (TGF-β2). Finally, the humanized mouse model was generated to study the effects of simvastatin-mediated immunotherapy in treating endometrial cancer. The protein expressions of TGF-β2, CD56, CD8, and PD-L1 in xenograft tumors were analyzed by Western blot or immunohistochemistry assay. In this study, simvastatin inhibited the proliferation of endometrial cancer cells (HEC-1 A and RL95-2) and EmCaMSCs, and the half-maximal inhibitory concentration (IC50) values of EmCaMSCs were much higher. Simvastatin rescued the proliferation and the population of CD8 + T cells and natural killer (NK) cells from PBMC coculturing with EmCaMSC. Simvastatin treatment reduced the expression of TGF-β2 in EmCaMSCs at both the gene and protein levels. TGF-β2 activated the downstream SMAD2/3 signaling, and their inhibition by simvastatin could enhance the cytotoxicity of NK cells against endometrial cancer cells in vitro. Additionally, a combination of simvastatin and NK cell therapy inhibited xenograft growth, potentially by reducing TGF-β2 expression. In conclusion, simvastatin could rescue the population of CD8 + T cells and NK cells from PBMC cocultured with EmCaMSCs. Furthermore, simvastatin could enhance the cytotoxicity of NK cells in vitro and inhibit tumor growth in vivo in a humanized mouse model. These results suggested that simvastatin may be considered as a repurposed and combination drug for treating endometrial cancer.
辛伐他汀是一种3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂，用于治疗心血管疾病，可降低低密度脂蛋白胆固醇，可能在癌症治疗中具有新的作用。然而，辛伐他汀对子宫内膜癌的影响仍存在争议。我们旨在阐明辛伐他汀在调节先前鉴定的子宫内膜癌相关间充质干细胞（EmCaMSCs）介导的免疫抑制作用和抗肿瘤进展中的作用及机制。采用EmCaMSCs与外周血单个核细胞（PBMC）共培养的方法检测CD8⁺T细胞、自然杀伤（NK）细胞的数量及NK细胞的细胞毒性。通过应用重组蛋白和候选蛋白转化生长因子-β2（TGF-β2）的抑制剂来阐明其机制。最后，构建人源化小鼠模型，研究辛伐他汀介导的免疫疗法治疗子宫内膜癌的效果。通过蛋白质印迹法或免疫组织化学分析移植瘤中TGF-β2、CD56、CD8和PD-L1的蛋白表达。在本研究中，辛伐他汀抑制子宫内膜癌细胞（HEC-1 A和RL95-2）和EmCaMSCs的增殖，EmCaMSCs的半数抑制浓度（IC50）值更高。辛伐他汀使与EmCaMSC共培养的PBMC中CD8⁺T细胞和自然杀伤（NK）细胞的增殖及数量恢复。辛伐他汀处理在基因和蛋白水平均降低了EmCaMSCs中TGF-β2的表达。TGF-β2激活下游SMAD2/3信号通路，辛伐他汀对其抑制可增强体外NK细胞对子宫内膜癌细胞的细胞毒性。此外，辛伐他汀与NK细胞疗法联合使用可抑制移植瘤生长，可能是通过降低TGF-β2表达实现的。总之，辛伐他汀可使与EmCaMSCs共培养的PBMC中CD8⁺T细胞和NK细胞的数量恢复。此外，辛伐他汀可增强体外NK细胞的细胞毒性，并在人源化小鼠模型中抑制体内肿瘤生长。这些结果表明，辛伐他汀可被视为一种用于治疗子宫内膜癌的重新利用的联合药物。
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