Targeting tumor-initiating cells: eliminating anabolic cancer stem cells with inhibitors of protein synthesis or by mimicking caloric restriction.
Targeting tumor-initiating cells: eliminating anabolic cancer stem cells with inhibitors of protein synthesis or by mimicking caloric restriction.
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DOI：
10.18632/oncotarget.3278
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发表时间：
2015-03-10
期刊：
影响因子：
--
通讯作者：
Sotgia F
中科院分区：
文献类型：
--
作者：
Lamb R;Harrison H;Smith DL;Townsend PA;Jackson T;Ozsvari B;Martinez-Outschoorn UE;Pestell RG;Howell A;Lisanti MP;Sotgia F
我们使用了一种无偏倚的蛋白质组学分析策略来确定肿瘤启动细胞（TICs），即癌症干细胞（CSCs）中的新的潜在治疗靶点。为此，我们直接将两种乳腺癌细胞系的乳腺球体的蛋白质组与附着的单层细胞进行了比较。这使我们能够鉴定出在csc和/或祖细胞中高度过度表达的蛋白质。我们将重点放在核糖体蛋白和蛋白折叠伴侣蛋白上，因为它们在乳房微球中明显过表达。总的来说，我们确定了bbbb80分子与蛋白质合成特异性相关，这些分子在乳房微球中普遍上调。这些蛋白中的大多数也在人乳腺癌细胞中转录上调，为其潜在的临床相关性提供了证据。因此，mRNA翻译量的增加可能为促进tic增殖克隆扩增提供了一种新的机制。通过三种独立的方法，使用已知的蛋白质合成抑制剂，对蛋白质组学研究结果进行了功能验证。例如，purromycin（一种模仿trna结构并竞争性抑制蛋白质合成的药物）在乳腺球体和单层培养物中优先靶向CSCs，其根除tic的效力比“大量”癌细胞高10倍。此外，在纳摩尔浓度下，抑制mTOR和蛋白质合成的雷帕霉素在减少乳房球形成方面非常有效。最后，蛋氨酸限制也明显抑制了乳腺球的形成，这模仿了培养细胞中热量限制的积极作用。值得注意的是，乳球形成对蛋氨酸限制和替代的敏感性是单层细胞增殖的18倍。蛋氨酸是蛋白质合成所必需的，因为每个蛋白质序列都以蛋氨酸残基开始。因此，CSCs的增殖和存活对蛋白质合成的抑制非常敏感，使用多种独立的方法。我们的研究结果具有重要的临床意义，因为它们也可以解释pi3激酶抑制剂和AKT抑制剂的积极治疗效果，因为它们最终会聚集在mTOR信号上并阻断蛋白质合成。我们得出结论，通过药物或蛋白质/蛋氨酸限制来抑制mRNA翻译可能是消除tic的有效策略。我们的数据还表明了一种新的机制，即热量/蛋白质限制可以通过靶向合成代谢肿瘤启动癌细胞中的蛋白质合成来减少肿瘤生长。
We have used an unbiased proteomic profiling strategy to identify new potential therapeutic targets in tumor-initiating cells (TICs), a.k.a., cancer stem cells (CSCs). Towards this end, the proteomes of mammospheres from two breast cancer cell lines were directly compared to attached monolayer cells. This allowed us to identify proteins that were highly over-expressed in CSCs and/or progenitor cells. We focused on ribosomal proteins and protein folding chaperones, since they were markedly over-expressed in mammospheres. Overall, we identified >80 molecules specifically associated with protein synthesis that were commonly upregulated in mammospheres. Most of these proteins were also transcriptionally upregulated in human breast cancer cells in vivo, providing evidence for their potential clinical relevance. As such, increased mRNA translation could provide a novel mechanism for enhancing the proliferative clonal expansion of TICs. The proteomic findings were functionally validated using known inhibitors of protein synthesis, via three independent approaches. For example, puromycin (which mimics the structure of tRNAs and competitively inhibits protein synthesis) preferentially targeted CSCs in both mammospheres and monolayer cultures, and was ~10-fold more potent for eradicating TICs, than “bulk” cancer cells. In addition, rapamycin, which inhibits mTOR and hence protein synthesis, was very effective at reducing mammosphere formation, at nanomolar concentrations. Finally, mammosphere formation was also markedly inhibited by methionine restriction, which mimics the positive effects of caloric restriction in cultured cells. Remarkably, mammosphere formation was >18-fold more sensitive to methionine restriction and replacement, as directly compared to monolayer cell proliferation. Methionine is absolutely required for protein synthesis, since every protein sequence starts with a methionine residue. Thus, the proliferation and survival of CSCs is very sensitive to the inhibition of protein synthesis, using multiple independent approaches. Our findings have important clinical implications, since they may also explain the positive therapeutic effects of PI3-kinase inhibitors and AKT inhibitors, as they ultimately converge on mTOR signaling and would block protein synthesis. We conclude that inhibition of mRNA translation by pharmacological or protein/methionine restriction may be effective strategies for eliminating TICs. Our data also indicate a novel mechanism by which caloric/protein restriction may reduce tumor growth, by targeting protein synthesis in anabolic tumor-initiating cancer cells.
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影响因子：
7.4
作者：
Fillmore, Christine M.;Kuperwasser, Charlotte
通讯作者：
Kuperwasser, Charlotte
影响因子：
2.5
作者：
Dean, Michael
通讯作者：
Dean, Michael
DOI：
10.1073/pnas.71.4.1133
发表时间：
1974-01-01
影响因子：
11.1
作者：
HALPERN, BC;CLARK, BR;SMITH, RA
通讯作者：
SMITH, RA
影响因子：
14.9
作者：
Greasley, PJ;Bonnard, C;Amati, B
通讯作者：
Amati, B
影响因子：
64.8
作者：
Barna, Maria;Pusic, Aya;Zollo, Ornella;Costa, Maria;Kondrashov, Nadya;Rego, Eduardo;Rao, Pulivarthi H.;Ruggero, Davide
通讯作者：
Ruggero, Davide