Gefitinib resistance in triple negative breast cancer (TNBC) is a growing important concern. Glutathione peroxidase 4 (GPX4) is a main regulator of ferroptosis, which is pivotal for TNBC cell growth. We investigated GPX4-mediated ferroptosis in gefitinib sensitivity in TNBC. Gefitinib resistant TNBC cells MDA-MB-231/Gef and HS578T/Gef were constructed and treated with lentivirus sh-GPX4 and ferroptosis inhibitor ferrostatin-1. GPX4 expression, cell viability and apoptosis were detected. Malondialdehyde (MDA), glutathione (GSH), reactive oxygen species (ROS) levels were evaluated. The levels of ferroptosis-related proteins were detected. Subcutaneous tumor model was established in nude mice, and gefitinib was intraperitoneally injected to evaluate tumor growth, apoptosis, and Ki-67 expression. GPX4 was increased in gefitinib-resistant cells. After silencing GPX4, the inhibition rate of cell viability was increased, the limitation of colony formation ability was reduced, apoptosis rate was increased, and the sensitivity of cells to gefitinib was improved. After silencing GPX4, MDA and ROS production were increased, while GSH was decreased. Silencing GPX4 promoted ferroptosis. Inhibition of GPX4 promoted gefitinib sensitivity by promoting cell ferroptosis. In vivo experiments also revealed that inhibition of GPX4 enhanced the anticancer effect of gefitinib through promoting ferroptosis. Overall, inhibition of GPX4 stimulated ferroptosis and enhanced TNBC cell sensitivity to gefitinib.

译文

:吉非替尼在三阴性乳腺癌(TNBC)中的耐药性日益受到关注。谷胱甘肽过氧化物酶4(GPX4)是铁质增生的主要调节剂,对TNBC细胞的生长至关重要。我们调查了吉非替尼在TNBC中GPX4介导的肥大症。构建了耐吉非替尼的TNBC细胞MDA-MB-231 / Gef和HS578T / Gef,并用慢病毒sh-GPX4和促肥大抑制剂ferrostatin-1处理。检测GPX4的表达,细胞活力和凋亡。评估了丙二醛(MDA),谷胱甘肽(GSH),活性氧(ROS)的水平。检测到与受精症相关的蛋白质水平。在裸鼠中建立皮下肿瘤模型,并腹膜内注射吉非替尼以评估肿瘤的生长,凋亡和Ki-67表达。吉非替尼耐药细胞中GPX4升高。 GPX4沉默后,细胞活力的抑制率增加,集落形成能力的局限性降低,细胞凋亡率增加,细胞对吉非替尼的敏感性提高。将GPX4沉默后,MDA和ROS产量增加,而GSH降低。沉默GPX4会促进ferroptosis。抑制GPX4通过促进细胞肥大症而促进了吉非替尼敏感性。体内实验还显示,抑制GPX4可通过促进ferroptosis来增强吉非替尼的抗癌作用。总体而言,抑制GPX4可刺激肥大症,并增强TNBC细胞对吉非替尼的敏感性。

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