Peroxynitrite Production Induced by LPS and X-ray Treatment Enhances Cellular Incorporation of Porphyrin in Mouse RAW264 Macrophages
Peroxynitrite Production Induced by LPS and X-ray Treatment Enhances Cellular Incorporation of Porphyrin in Mouse RAW264 Macrophages
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DOI：
10.3390/app11083503
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发表时间：
2021-04-01
影响因子：
2.7
通讯作者：
Ito, Hiromu
中科院分区：
文献类型：
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作者：
Ito, Hiromu
光动力疗法（PDT）是一种微创癌症疗法，将癌细胞中卟啉等光敏剂的积累与激光照射相结合。我之前曾报道过，线粒体衍生的活性氧 (ROS) 调节卟啉转运蛋白、血红素载体蛋白 1 (HCP1) 的表达，并增加癌细胞中卟啉的积累。据报道，含有活化巨噬细胞（称为肿瘤相关巨噬细胞（TAM））的肿瘤会增加恶性程度。 TAM 通过诱导型 NO 合酶 (iNOS) 的表达产生一氧化氮 (NO)，以及 NO 与超氧化物反应产生的高活性氮物质过氧亚硝酸盐。在这里，我研究了鼠巨噬细胞系 RAW264 中过氧亚硝酸盐、HCP1 表达和胞内卟啉摄取之间的关系。 RAW264 细胞经脂多糖 (LPS) 处理后被激活，导致 iNOS 表达和 NO 产生增加。额外的 X 射线照射导致 ROS 的产生以及随后的过氧亚硝酸盐的产生。重要的是，LPS 和 X 射线共同处理显着增强了细胞中 HCP1 的表达和卟啉积累，表明过氧亚硝酸盐上调了卟啉转运蛋白 HCP1。因此，PDT 可以有效地靶向 TAM，并且靶向巨噬细胞激活的药物通常可以抑制肿瘤进展。
Photodynamic therapy (PDT) is a minimally invasive cancer therapy that combines the accumulation of photosensitizers such as porphyrins in cancer cells with laser irradiation. I have previously reported that mitochondrially derived reactive oxygen species (ROS) regulate the expression of a porphyrin transporter, heme carrier protein 1 (HCP1), and increase porphyrin accumulation in cancer cells. Tumors that contain activated macrophages, referred to as tumor-associated macrophages (TAMs), have been reported to have increased malignancy. TAMs produce nitric oxide (NO), via the expression of inducible NO synthase (iNOS), and the highly reactive nitrogen species, peroxynitrite, which is produced by the reaction of NO with superoxide. Here, I examined the relationship between peroxynitrite, HCP1 expression, and intracellular porphyrin uptake in the murine macrophage cell line RAW264. RAW264 cells were activated by lipopolysaccharide (LPS) treatment which resulted in increased iNOS expression and NO production. Additional X-ray irradiation resulted in the generation of ROS and the subsequent generation of peroxynitrite. Importantly, LPS and X-ray co-treatment significantly enhanced HCP1 expression and porphyrin accumulation in cells, suggesting that the peroxynitrite upregulates the porphyrin transporter, HCP1. Therefore, TAMs may be effectively targeted with PDT, and tumor progression may be suppressed in general by agents that target the activation of macrophages.