Rg3 inhibits gemcitabine-induced lung cancer cell invasiveness through ROS-dependent, NF-B- and HIF-1-mediated downregulation of PTX3
Rg3 inhibits gemcitabine-induced lung cancer cell invasiveness through ROS-dependent, NF-B- and HIF-1-mediated downregulation of PTX3
复制标题
DOI：
10.1002/jcp.27731
复制
发表时间：
2019-07-01
影响因子：
5.6
通讯作者：
Yan, Qiu
中科院分区：
文献类型：
--
作者：
Ahmmed, Bulbul;Kampo, Sylvanus;Yan, Qiu
PTX 3是长五聚体蛋白亚家族的成员，与先天免疫相关，对于抵抗某些癌症是不可或缺的。吉西他滨是阿糖胞苷的类似物，由于严重的耐药性，其获益有限。人肺癌细胞中GEM上的PTX 3表达尚未阐明;本研究旨在通过不同的机制显示活性氧（ROS）介导的PTX 3表达。而Rg 3是一种具有较强抗肿瘤活性的中草药。此外，我们测试了这一假设; Rg 3消除了GEM诱导的ROS介导的Akt和细胞外信号调节激酶（ERK）途径的激活，并抑制核因子κ B（NF-B）和HIF-1的核堆积。在时间和剂量依赖性方式的基础上，我们的数据表明，GEM诱导的PTX 3表达依赖于ROS的产生，因为它被用自由基清除剂N-乙酰基-L-半胱氨酸预处理肺癌细胞所消除。我们的数据表明，通过GEM上调PTX 3与由磷酸化诱导的IB降解导致的核中NF-B和HIF-1的时间依赖性增加相关，而HIF-1上调是NF-B依赖性的。GEM处理的肺癌细胞中ROS表达的增加先于NF-B和HIF-1的核积累，而ROS的抑制减弱了这些作用。ERK 1/2和Akt激活介导ROS对NF-B和HIF-1的作用，其药理学抑制抑制GEM诱导的PTX 3。我们的研究结果加强了PTX 3信号在GEM诱导的耐药性中的作用，并指出了化疗的非预期和不希望的效果，并获得了积极的治疗方案;协同作用与肺癌中的NF-B下调有关。
PTX3, a member of the long pentraxin subfamily, associated with innate immunity is indispensable for resistance to some cancer. Gemcitabine, an analog of cytosine arabinoside, has shown restrained benefits because of profound chemoresistance. The PTX3 expression on GEM in human lung cancer cells have not yet been clarified; the present study aimed to show reactive oxygen species (ROS) mediatory PTX3 expression through distinct mechanisms. Whereas ginsenoside Rg3 is a herbal medicine with strong antitumor activity. Furthermore, we tested the hypothesis; Rg3 abrogates GEM-induced production of ROS-mediated activation of Akt and extracellular signal-regulated kinase (ERK) pathways and inhibits nuclear piling-up of nuclear factor kappa B (NF-B) and HIF-1. On the basis of time and dose-dependent manner, our data demonstrated that GEM-induced PTX3 expression was dependent on ROS generation as it was abrogated by pretreatment of lung cancer cells with the free radical scavenger N-acetyl-l-cysteine. Our data demonstrated that PTX3 upregulation by GEM correlated with the time-dependent escalation of NF-B and HIF-1 in the nucleus resulted from phosphorylation-induced degradation of IB, whereas HIF-1 upregulation was NF-B-dependent. Increase in ROS expression in lung cancer cells on GEM treatment preceded the nuclear accumulation of NF-B and HIF-1 and suppression of ROS diminished these effects. ERK1/2 and Akt activation mediated the effect of ROS on NF-B and HIF-1 and their pharmacological inhibition suppressed GEM-induced PTX3. Our study findings reinforced the role regarding PTX3 signaling in GEM-induced resistance and pointed toward an unintended and undesired effect of chemotherapy and to get an active regimen; the synergy was associated with NF-B downregulation in lung cancer.