HES1-mediated inhibition of Notchl signaling by a Gemini vitamin D analog leads to decreased CD44+/CD24-/low tumor-initiating subpopulation in basal-like breast cancer

被引:36
作者
So, Jae Young [1 ]
Wahler, Joseph [1 ]
Das Gupta, Soumyasri [1 ]
Salerno, David M. [1 ]
Maehr, Hubert [1 ]
Uskokovic, Milan [1 ]
Suh, Nanjoo [1 ,2 ]
机构
[1] Rutgers State Univ, Ernest Mario Sch Pharm, Dept Biol Chem, Piscataway, NJ 08854 USA
[2] Rutgers Canc Inst New Jersey, New Brunswick, NJ USA
关键词
Notch signaling; Tumor-initiating cells; Gemini vitamin D analog; CD44(+)/CD24(-/low) cells; HES1; Breast cancer; DIFFERENT SIDE-CHAINS; MAMMARY TUMORIGENESIS; CALCITRIOL DERIVATIVES; ESTROGEN-RECEPTOR; PROGENITOR CELLS; MESSENGER-RNA; C-MYC; EXPRESSION; TARGET; DIFFERENTIATION;
D O I
10.1016/j.jsbmb.2014.12.013
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Tumor-initiating cells (also known as cancer stem cells) are the subpopulation of cells shown to be responsible for tumor initiation, maintenance and recurrence. In breast cancer, CD44(+)/CD24(-/low) cells were identified as tumor-initiating cells. We previously reported that a Gemini vitamin D analog, 1,25-dihydroxy-20R-21(3-hydroxy-3-deuteromethyl-4,4,4-trideuterobutyl)-23-yne-26,27-hexafluoro-cholecalciferol (BXL0124), reduced CD44(+)/CD24(-/low) cells in MCF10DCIS basal-like breast cancer cells. Since Notch has been identified as one of the key signaling pathways involved in breast cancer stem cells, the effect of BXL0124 on the Notch signaling pathway was investigated in breast cancer. The CD44(+)/CD24(-/low) subpopulation of MCF10DCIS cells showed elevated Notch1 signaling and increased cell proliferation compared to the CD44(+)/CD24(high) subpopulation. Treatment with the Gemini vitamin D analog BXL0124 decreased the level of activated Notch1 receptor. In addition, mRNA and protein levels of the Notch ligands, Jagged-1, Jagged-2 and DLL1, were significantly reduced by treatment with BXL0124, which was followed by repression of c-Myc, a key downstream target of Notch signaling. Interestingly, HES1, a known downstream target of Notch signaling, was rapidly induced by treatment with BXL0124. The inhibitory effect of BXL0124 on Notch signaling was reversed by knockdown of HES1. Overexpression of HES1 inhibited Notch1 signaling and reduced the CD44(+)/CD24(-/low) subpopulation, confirming a role of HES1 in Notch1 signaling. In conclusion, the Gemini vitamin D analog, BXL0124, represses the tumor-initiating subpopulation by HES1-mediated inhibition of Notch1 signaling. The present study demonstrates BXL0124 as a potent inhibitor of Notch signaling to target tumor-initiating cells in basal-like breast cancer. This article is part of a Special Issue entitled "17th Vitamin D Workshop". (C) 2014 Elsevier Ltd. All rights reserved.
引用
收藏
页码:111 / 121
页数:11
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