PDF(Pubmed)
Abstract：
The strategy for treating bladder cancer (BC) depends on whether there is muscle invasion or not, with the latter mostly treated with intravesical therapy, such as with bacillus Calmette-Guérin (BCG). However, BCG treatment is unsuccessful in 70% of patients, who are then subjected to radical cystectomy. Although immune-checkpoint inhibitors have been approved as a second-line therapy for a subset of BC patients, these have failed to meet primary endpoints in clinical trials. Thus, it is crucial to find a new treatment. The mitochondrial gatekeeper protein, the voltage-dependent anion channel 1 (VDAC1), mediates metabolic crosstalk between the mitochondria and cytosol and is involved in apoptosis. It is overexpressed in many cancer types, as shown here for BC, pointing to its significance in high-energy-demanding cancer cells. The BC cell lines UM-UC3 and HTB-5 express high VDAC1 levels compared to other cancer cell lines. VDAC1 silencing in these cells using siRNA that recognizes both human and mouse VDAC1 (si-m/hVDAC1-B) reduces cell viability, mitochondria membrane potential, and cellular ATP levels. Here, we used two BC mouse models: subcutaneous UM-UC3 cells and chemically induced BC using the carcinogen N-Butyl-N-(4-hydroxybutyl) nitrosamine (BBN). Subcutaneous UM-UC3-derived tumors treated with si-m/hVDAC1 showed inhibited tumor growth and reprogrammed metabolism, as reflected in the reduced expression of metabolism-related proteins, including Glut1, hexokinase, citrate synthase, complex-IV, and ATP synthase, suggesting reduced metabolic activity. Furthermore, si-m/hVDAC1-B reduced the expression levels of cancer-stem-cell-related proteins (cytokeratin-14, ALDH1a), modifying the tumor microenvironment, including decreased angiogenesis, extracellular matrix, tumor-associated macrophages, and inhibited epithelial-mesenchymal transition. The BBN-induced BC mouse model showed a clear carcinoma, with damaged bladder morphology and muscle-invasive tumors. Treatment with si-m/hVDAC1-B encapsulated in PLGA-PEI nanoparticles that were administered intravesically directly to the bladder showed a decreased tumor area and less bladder morphology destruction and muscle invasion. Overall, the obtained results point to the potential of si-m/hVDAC1-B as a possible therapeutic tool for treating bladder cancer.
摘要：
治疗膀胱癌（BC）的策略取决于是否有肌肉浸润，后者主要用膀胱内治疗，例如卡介苗(BCG)。然而,70%的患者卡介苗治疗不成功，然后接受根治性膀胱切除术。尽管免疫检查点抑制剂已被批准为部分BC患者的二线治疗，这些指标未能达到临床试验的主要终点.因此，找到新的治疗方法至关重要。线粒体看门人蛋白，电压依赖性阴离子通道1(VDAC1)，介导线粒体和细胞质之间的代谢串扰，并参与细胞凋亡。它在许多癌症类型中过度表达，如BC所示，指出了它在高能量要求的癌细胞中的重要性。与其他癌细胞系相比,BC细胞系UM-UC3和HTB-5表达高VDAC1水平。使用识别人和小鼠VDAC1的siRNA（si-m/hVDAC1-B）在这些细胞中沉默VDAC1降低细胞活力，线粒体膜电位，和细胞ATP水平。这里,我们使用了两种BC小鼠模型：皮下UM-UC3细胞和使用致癌物N-丁基-N-（4-羟基丁基）亚硝胺（BBN）的化学诱导BC。用si-m/hVDAC1治疗的皮下UM-UC3衍生的肿瘤显示出抑制肿瘤生长和重新编程的代谢，正如代谢相关蛋白表达减少所反映的那样，包括Glut1，己糖激酶，柠檬酸合成酶，complex-IV,和ATP合成酶,表明代谢活动减少。此外，si-m/hVDAC1-B降低了癌症干细胞相关蛋白（细胞角蛋白14，ALDH1a）的表达水平，改变肿瘤微环境，包括血管生成减少,细胞外基质，肿瘤相关巨噬细胞，并抑制上皮-间质转化。BBN诱导的BC小鼠模型显示清晰的癌，膀胱形态受损和肌肉浸润性肿瘤。用包封在PLGA-PEI纳米颗粒中的si-m/hVDAC1-B直接膀胱施用至膀胱的治疗显示出减少的肿瘤面积和较少的膀胱形态破坏和肌肉侵入。总的来说,获得的结果表明si-m/hVDAC1-B作为治疗膀胱癌的可能治疗工具的潜力.
