Tu Chih-Chieh, Hsieh Tsung-Han, Chu Cheng-Ying, Lin Yu-Chen, Lin Bo-Jyun, Chen Chun-Han
Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Cell Death Dis. 2024 Dec 18;15(12):908. doi: 10.1038/s41419-024-07298-x.
Bladder cancer (BC) is the second most prevalent genitourinary malignancy worldwide. Despite recent approvals of immune checkpoint inhibitors and targeted therapy for muscle invasive or recurrent BC, options remain limited for patients with non-muscle invasive BC (NMIBC) refractory to Bacillus Calmette-Guérin (BCG) and chemotherapy. NMIBC is more frequently classified as a luminal subtype, in which increased PPARγ activity is a key feature in promoting tumor growth and evasion of immunosurveillance. Cinobufotalin is one of the major compound of bufadienolides, the primary active components of toad venom that has been utilized in the clinical treatment of cancer. We herein focused on cinobufotalin, examining its anticancer activity and molecular mechanisms in luminal-type NMIBC. Our results newly reveal that cinobufotalin strongly suppresses the viability and proliferation of luminal BC cells with minimal cytotoxic effects on normal uroepithelial cells, and exhibits significant antitumor activity in a RT112 xenograft BC model. Mechanistically, our sub-G1-phase cell accumulation, Annexin V staining, caspase-3/8/9 activation, and PARP activation analyses show that cinobufotalin induces apoptosis in luminal-type BC cells. Cinobufotalin significantly inhibited the levels of PPARγ and its downstream targets, as well as lipid droplet formation and free fatty acid levels in RT112 cells. PPARγ overexpression rescued RT112 cells from cinobufotalin-induced apoptosis and mitigated the downregulation of FASN and PLIN4. Finally, we show seemingly for the first time that cinobufotalin promotes SIAH1/2-mediated proteasomal degradation of PPARγ in luminal BC cells. Together, these findings compellingly support the idea that cinobufotalin could be developed as a promising therapeutic agent for treating luminal-type NMIBC.
膀胱癌（BC）是全球第二大常见的泌尿生殖系统恶性肿瘤。尽管最近免疫检查点抑制剂和靶向治疗已被批准用于肌肉浸润性或复发性膀胱癌，但对于卡介苗（BCG）和化疗难治的非肌肉浸润性膀胱癌（NMIBC）患者，治疗选择仍然有限。NMIBC更常被归类为管腔亚型，其中过氧化物酶体增殖物激活受体γ（PPARγ）活性增加是促进肿瘤生长和逃避免疫监视的关键特征。华蟾酥毒基是蟾毒配基类的主要化合物之一，蟾毒配基是蟾蜍毒液的主要活性成分，已用于癌症的临床治疗。我们在此聚焦于华蟾酥毒基，研究其在管腔型NMIBC中的抗癌活性和分子机制。我们的结果首次揭示，华蟾酥毒基强烈抑制管腔型膀胱癌细胞的活力和增殖，对正常尿路上皮细胞的细胞毒性作用最小，并在RT112异种移植膀胱癌模型中表现出显著的抗肿瘤活性。从机制上讲，我们的亚G1期细胞积累、膜联蛋白V染色、半胱天冬酶-3/8/9激活和聚（ADP-核糖）聚合酶（PARP）激活分析表明，华蟾酥毒基诱导管腔型膀胱癌细胞凋亡。华蟾酥毒基显著抑制RT112细胞中PPARγ及其下游靶点的水平，以及脂滴形成和游离脂肪酸水平。PPARγ过表达使RT112细胞免受华蟾酥毒基诱导的凋亡，并减轻脂肪酸合酶（FASN）和脂滴包被蛋白4（PLIN4）的下调。最后，我们似乎首次表明，华蟾酥毒基促进管腔型膀胱癌细胞中SIAH1/2介导的PPARγ蛋白酶体降解。总之，这些发现有力地支持了华蟾酥毒基可被开发为治疗管腔型NMIBC的有前景治疗药物这一观点。
