A novel chalcone derivative has antitumor activity in melanoma by inducing DNA damage through the upregulation of ROS products
A novel chalcone derivative has antitumor activity in melanoma by inducing DNA damage through the upregulation of ROS products
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DOI：
10.1186/s12935-020-1114-5
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发表时间：
2020-01-30
影响因子：
5.8
通讯作者：
Peng, Cong
中科院分区：
文献类型：
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作者：
Li, Keke;Zhao, Shuang;Peng, Cong
黑色素瘤是侵袭性最强的肿瘤之一，对传统化疗和放疗具有显著的耐药性。虽然靶向治疗和免疫治疗有利于晚期黑色素瘤患者的治疗，但已经观察到BRAFi （BRAF抑制剂）耐药性和免疫治疗的低反应率或严重副作用，因此有必要开发新的黑色素瘤治疗抑制剂。方法采用cck8和集落形成法检测lj-1-59在不同黑色素瘤细胞中的增殖情况。为了进一步探讨lj-1-59在黑色素瘤中的作用机制，我们进行了RNA测序，发现差异基因富集的途径。Western blot和Q-RT-PCR证实了lj-1-59在黑色素瘤中的功能。结果lj-1-59在体外和体内均能抑制黑色素瘤细胞增殖，诱导细胞周期阻滞在G2/M期，促进黑色素瘤细胞凋亡。此外，通过RNA-Seq研究lj-1-59治疗黑色素瘤细胞后基因表达谱的变化，发现该化合物调节多种途径，如DNA复制、P53、凋亡和细胞周期。此外，我们通过Q-RT-PCR验证了lj-1-59对关键基因表达改变的影响。我们的研究结果表明，lj-1-59显著增加ROS（活性氧）产物，导致黑色素瘤细胞系的DNA毒性。此外，lj-1-59增加BRAFi耐药黑色素瘤细胞中的ROS水平，导致DNA损伤，导致G2/M期阻滞和细胞凋亡。综上所述，我们发现lj-1-59治疗通过增加ROS水平诱导细胞凋亡和DNA损伤来抑制黑色素瘤细胞生长，提示该化合物是一种潜在的黑色素瘤治疗药物。
Background Melanoma is one of the most aggressive tumors with the remarkable characteristic of resistance to traditional chemotherapy and radiotherapy. Although targeted therapy and immunotherapy benefit advanced melanoma patient treatment, BRAFi (BRAF inhibitor) resistance and the lower response rates or severe side effects of immunotherapy have been observed, therefore, it is necessary to develop novel inhibitors for melanoma treatment. Methods We detected the cell proliferation of lj-1-59 in different melanoma cells by CCK 8 and colony formation assay. To further explore the mechanisms of lj-1-59 in melanoma, we performed RNA sequencing to discover the pathway of differential gene enrichment. Western blot and Q-RT-PCR were confirmed to study the function of lj-1-59 in melanoma. Results We found that lj-1-59 inhibits melanoma cell proliferation in vitro and in vivo, induces cell cycle arrest at the G2/M phase and promotes apoptosis in melanoma cell lines. Furthermore, RNA-Seq was performed to study alterations in gene expression profiles after treatment with lj-1-59 in melanoma cells, revealing that this compound regulates various pathways, such as DNA replication, P53, apoptosis and the cell cycle. Additionally, we validated the effect of lj-1-59 on key gene expression alterations by Q-RT-PCR. Our findings showed that lj-1-59 significantly increases ROS (reactive oxygen species) products, leading to DNA toxicity in melanoma cell lines. Moreover, lj-1-59 increases ROS levels in BRAFi -resistant melanoma cells, leading to DNA damage, which caused G2/M phase arrest and apoptosis. Conclusions Taken together, we found that lj-1-59 treatment inhibits melanoma cell growth by inducing apoptosis and DNA damage through increased ROS levels, suggesting that this compound is a potential therapeutic drug for melanoma treatment.