Alterations in cellular metabolism are vital for cancer cell growth and motility. Here, we focused on metabolic reprogramming and changes in tumor hallmarks in lung cancer by silencing the expression of the mitochondrial gatekeeper VDAC1. To better mimic the clinical situation of lung cancer, we induced lung cancer in A/J mice using the carcinogen urethane and examined the effectiveness of si-m/hVDAC1-B encapsulated in PLGA-PEI nanoparticles. si-m/hVDAC1-B, given intravenously, induced metabolism reprogramming and inhibited tumor growth as monitored using MRI. Mice treated with non-targeted (NT) PLGA-PEI-si-NT showed many large size tumors in the lungs, while in PLGA-PEI-si-m/hVDAC-B-treated mice, lung tumor number and area were markedly decreased. Immunofluorescence staining showed decreased expression of VDAC1 and metabolism-related proteins and altered expression of cancer stem cell markers. Morphological analysis showed two types of tumors differing in their morphology; cell size and organization within the tumor. Based on specific markers, the two tumor types were identified as small cell (SCLC) and non-small cell (NSCLC) lung cancer. These two types of tumors were found only in control tumors, suggesting that PLGA-PEI-si-m/hVDAC1-B also targeted SCLC. Indeed, using a xenograft mouse model of human-derived SCLC H69 cells, si-m/hVDAC1-B inhibited tumor growth and reduced the expression of VDAC1 and energy- and metabolism-related enzymes, and of cancer stem cells in the established xenograft. Additionally, intravenous treatment of urethane-induced lung cancer mice with the VDAC1-based peptide, Retro-Tf-D-LP4, showed inhibition of tumor growth, and decreased expression levels of metabolism- and cancer stem cells-related proteins. Thus, silencing VDAC1 targeting both NSCLC and SCLC points to si-VDAC1 as a possible therapeutic tool to treat these lung cancer types. This is important as target NSCLC tumors undergo transformation to SCLC.
细胞代谢的改变对癌细胞的生长和运动至关重要。本研究通过沉默线粒体守门蛋白VDAC1的表达，聚焦于肺癌中的代谢重编程及肿瘤标志物的变化。为更好地模拟肺癌的临床情况，我们使用致癌物氨基甲酸乙酯诱导A/J小鼠发生肺癌，并检测了封装于PLGA-PEI纳米颗粒中的si-m/hVDAC1-B的效果。静脉注射si-m/hVDAC1-B可诱导代谢重编程，并通过MRI监测证实其抑制肿瘤生长。接受非靶向PLGA-PEI-si-NT治疗的小鼠肺部出现大量大体积肿瘤，而经PLGA-PEI-si-m/hVDAC-B治疗的小鼠肺肿瘤数量和面积均显著减少。免疫荧光染色显示VDAC1及代谢相关蛋白表达下降，癌症干细胞标志物表达发生改变。形态学分析发现存在两种不同形态的肿瘤类型，其细胞大小和肿瘤内部组织结构存在差异。根据特异性标志物，这两种肿瘤被鉴定为小细胞肺癌和非小细胞肺癌。值得注意的是，这两种肿瘤类型仅出现在对照组中，提示PLGA-PEI-si-m/hVDAC1-B对SCLC也具有靶向作用。通过建立人源SCLC H69细胞的异种移植小鼠模型，证实si-m/hVDAC1-B能抑制肿瘤生长，降低VDAC1、能量代谢相关酶及癌症干细胞标志物的表达。此外，使用基于VDAC1的多肽Retro-Tf-D-LP4静脉治疗氨基甲酸乙酯诱导的肺癌小鼠，同样显示出抑制肿瘤生长、降低代谢及癌症干细胞相关蛋白表达水平的效果。因此，靶向沉默VDAC1对NSCLC和SCLC均具有抑制作用，表明si-VDAC1可能成为治疗这两种肺癌类型的潜在工具。这一发现具有重要意义，因为靶向治疗的NSCLC肿瘤可能转化为SCLC。
肿瘤(癌症)患者之家