Ramamoorthy Prabhu, Dandawate Prasad, Jensen Roy A, Anant Shrikant
Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Biomedicines. 2021 Apr 28;9(5):482. doi: 10.3390/biomedicines9050482.
Triple negative breast cancer (TNBC) is observed in ~15% of breast cancers and results in poor survival and increased distant metastases. Within the tumor are present a small portion of cancer stem cells that drive tumorigenesis and metastasis. In this study, we aimed to elucidate whether the two natural compounds, celastrol and triptolide, inhibit stemness in TNBC. MDA-MB-231, BT20, and a patient-derived primary cells (PD-TNBC) were used in the study. Mammosphere assay was performed to assess the stemness. Both celastrol and triptolide treatment suppressed mammosphere formation. Furthermore, the compound suppressed expression of cancer stem cell marker proteins DCLK1, ALDH1, and CD133. Notch signaling plays a critical role in stem cells renewal. Both celastrol or triptolide reduced Notch -1 activation and expression of its downstream target proteins HES-1 and HEY-1. However, when NICD 1 was ectopically overexpressed in the cells, it partially rescued proliferation and mammosphere formation of the cells, supporting the role of notch signaling. Together, these data demonstrate that targeting stem cells and the notch signaling pathway may be an effective strategy for curtailing TNBC progression.
三阴性乳腺癌（TNBC）约占乳腺癌的15%，其生存率低且远处转移增加。肿瘤内存在一小部分驱动肿瘤发生和转移的癌症干细胞。在本研究中，我们旨在阐明两种天然化合物，雷公藤红素和雷公藤甲素，是否能抑制TNBC中的干性。本研究使用了MDA-MB-231、BT20和患者来源的原代细胞（PD-TNBC）。进行了乳腺球形成实验以评估干性。雷公藤红素和雷公藤甲素处理均抑制了乳腺球的形成。此外，该化合物还抑制了癌症干细胞标志物蛋白DCLK1、ALDH1和CD133的表达。Notch信号在干细胞更新中起关键作用。雷公藤红素或雷公藤甲素均可降低Notch-1的激活及其下游靶蛋白HES-1和HEY-1的表达。然而，当在细胞中异位过表达NICD 1时，它部分挽救了细胞的增殖和乳腺球形成，支持了Notch信号的作用。总之，这些数据表明，靶向干细胞和Notch信号通路可能是遏制TNBC进展的有效策略。
