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首页> 外文学位 >Methionine Stress Induces Downregulation of Cdc6 and Pre-Replication Complexes and Activates Intrinsic Apoptosis in Breast Cancer Cells.
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Methionine Stress Induces Downregulation of Cdc6 and Pre-Replication Complexes and Activates Intrinsic Apoptosis in Breast Cancer Cells.

机译：蛋氨酸应激诱导Cdc6和复制前复合体的下调并激活乳腺癌细胞的固有凋亡。

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摘要

Methionine and homocysteine are metabolites in the transmethylation pathway leading to synthesis of the methyl-donor S-adenosylmethionine (SAM). Most cancer cells stop proliferating during methionine stress conditions - when methionine is replaced in the growth media by its immediate metabolic precursor homocysteine (Met-Hcy+). Non-transformed cells proliferate in Met-Hcy+ media making the methionine metabolic requirement of cancer cells an attractive target for therapy. To study this phenomenon in breast cancer cells we selected methionine independent resistant cell lines derived from MDAMB468 breast cancer cells. Resistant cells grew normally in Met-Hcy+ media, whereas their parental MDAMB468 cells rapidly arrested in the G1 phase. Remarkably, supplementing Met-Hcy+ growth media with S adenosylmethionine suppressed the cell proliferation defects, indicating that methionine stress is a consequence of SAM limitation rather than low amino acid concentrations. Accordingly, mTOR activity, the primary effector responding to amino acid limitation, remained high. However, we found that Cdc6 protein levels decreased and pre-replication complexes were destabilized in methionine stressed MDAMB468 but not resistant cells. The methionine stress induced G1 cell cycle arrest was maintained for several days before induction of intrinsic apoptosis and downstream caspase activation led to a significant decrease in cell number. We also created a mathematical model of methionine metabolism in yeast cells as a first step toward studying the equivalent pathway in silico in cancer cells. Our study characterizes metabolite requirements, cell cycle changes, and apoptosis induction during methionine stress and helps explain the metabolic uniqueness of cancer cells.
机译：蛋氨酸和高半胱氨酸是甲基转移途径中的代谢产物，导致合成了甲基供体S-腺苷甲硫氨酸（SAM）。当蛋氨酸在生长培养基中被其立即代谢的前体高半胱氨酸（Met-Hcy +）替代时，大多数癌细胞在蛋氨酸应激条件下会停止增殖。未转化的细胞在Met-Hcy +培养基中增殖，使癌细胞对蛋氨酸的代谢需求成为治疗的诱人靶标。为了研究乳腺癌细胞中的这种现象，我们选择了衍生自MDAMB468乳腺癌细胞的蛋氨酸非依赖性抗性细胞系。抗性细胞在Met-Hcy +培养基中正常生长，而其亲本MDAMB468细胞则迅速停滞在G1期。值得注意的是，用S腺苷甲硫氨酸补充Met-Hcy +生长培养基可抑制细胞增殖缺陷，这表明甲硫氨酸胁迫是SAM限制的结果，而不是低氨基酸浓度。因此，响应于氨基酸限制的主要效应子mTOR活性仍然很高。但是，我们发现在蛋氨酸应激的MDAMB468中，Cdc6蛋白水平下降，复制前复合物不稳定，而耐药细胞中则没有。在诱导内在凋亡和下游胱天蛋白酶激活导致细胞数量显着减少之前，蛋氨酸应激诱导的G1细胞周期停滞维持了几天。我们还建立了酵母细胞中蛋氨酸代谢的数学模型，作为研究癌细胞中计算机等效途径的第一步。我们的研究表征了蛋氨酸胁迫期间代谢产物的需求，细胞周期的变化和细胞凋亡的诱导，并有助于解释癌细胞的代谢独特性。

著录项

  • 作者

    Booher, Keith Richard.;

  • 作者单位

    University of California, Irvine.;

  • 授予单位 University of California, Irvine.;
  • 学科 Biology Molecular.;Chemistry Biochemistry.;Biology Systematic.
  • 学位 Ph.D.
  • 年度 2011
  • 页码 116 p.
  • 总页数 116
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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