Mevalonate Metabolism Regulates Basal Breast Cancer Stem Cells and Is a Potential Therapeutic Target
Mevalonate Metabolism Regulates Basal Breast Cancer Stem Cells and Is a Potential Therapeutic Target
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DOI：
10.1002/stem.1122
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发表时间：
2012-07-01
期刊：
影响因子：
5.2
通讯作者：
Charafe-Jauffret, Emmanuelle
中科院分区：
文献类型：
--
作者：
Ginestier, Christophe;Monville, Florence;Charafe-Jauffret, Emmanuelle
越来越多的证据表明，乳腺肿瘤是按等级组织的，其中有一类致瘤性癌细胞，即维持肿瘤生长的癌症干细胞（CSCs）。控制CSC行为的蛋白质网络的特征对于设计针对该细胞亚群的新治疗策略至关重要。我们试图确定从13种不同的乳腺癌细胞系（管腔或基底/间充质亚型）中分离的CSCs的特定分子途径。我们比较了在贴壁条件下生长的癌细胞与匹配肿瘤球培养的癌细胞的基因表达谱。由于来自管腔细胞系的肿瘤球传代中少量CSC富集，未发现在管腔肿瘤球中普遍调节的特异性途径。然而，在基底/间充质肿瘤球中，甲羟戊酸代谢途径的酶与同源贴壁细胞中的酶相比过度表达。用羟基-3-甲基戊二酰辅酶a还原酶阻滞剂抑制这一途径导致乳腺CSC的减少，而不依赖于胆固醇生物合成和蛋白质法尼化的抑制。对这一代谢途径的进一步调节表明，蛋白香叶酰化（GG）对乳腺CSC的维持至关重要。香叶基香叶基转移酶I （GGTI）酶的小分子抑制剂在体外和原发性乳腺癌异种移植中均可减少乳腺CSC亚群。我们发现GGTI对CSC亚群的影响是通过Ras同源家族成员A （RHOA）的失活和P27（kip1）在细胞核中的积累增加介导的。GG蛋白作为CSC维持的主要贡献者的鉴定为基础乳腺癌的CSC靶向治疗开辟了有希望的前景。干细胞2012；30:1327 - 1337
There is increasing evidence that breast tumors are organized in a hierarchy, with a subpopulation of tumorigenic cancer cells, the cancer stem cells (CSCs), which sustain tumor growth. The characterization of protein networks that govern CSC behavior is paramount to design new therapeutic strategies targeting this subpopulation of cells. We have sought to identify specific molecular pathways of CSCs isolated from 13 different breast cancer cell lines of luminal or basal/mesenchymal subtypes. We compared the gene expression profiling of cancer cells grown in adherent conditions to those of matched tumorsphere cultures. No specific pathway was identified to be commonly regulated in luminal tumorspheres, resulting from a minor CSC enrichment in tumorsphere passages from luminal cell lines. However, in basal/mesenchymal tumorspheres, the enzymes of the mevalonate metabolic pathway were over-expressed compared to those in cognate adherent cells. Inhibition of this pathway with hydroxy-3-methylglutaryl CoA reductase blockers resulted in a reduction of breast CSC independent of inhibition of cholesterol biosynthesis and of protein farnesylation. Further modulation of this metabolic pathway demonstrated that protein geranylgeranylation (GG) is critical to breast CSC maintenance. A small molecule inhibitor of the geranylgeranyl transferase I (GGTI) enzyme reduced the breast CSC subpopulation both in vitro and in primary breast cancer xenografts. We found that the GGTI effect on the CSC subpopulation is mediated by inactivation of Ras homolog family member A (RHOA) and increased accumulation of P27(kip1) in the nucleus. The identification of protein GG as a major contributor to CSC maintenance opens promising perspectives for CSC targeted therapy in basal breast cancer. STEM CELLS 2012;30:1327-1337