Selective amino acid restriction targets mitochondria to induce apoptosis of androgen-independent prostate cancer cells
Selective amino acid restriction targets mitochondria to induce apoptosis of androgen-independent prostate cancer cells
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DOI：
10.1002/jcp.20766
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发表时间：
2006-11-01
影响因子：
5.6
通讯作者：
Meadows, Gary G.
中科院分区：
文献类型：
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作者：
Fu, Ya-Min;Zhang, Hui;Meadows, Gary G.
相对特定氨基酸依赖性是癌细胞代谢异常之一，限制特定氨基酸会诱导前列腺癌细胞凋亡。这项研究表明，限制酪氨酸和苯丙氨酸（Tyr/Phe），谷氨酰胺（Gln），或蛋氨酸（Met），调节Raf和Akt的生存途径，并影响线粒体的功能，在DUI 45和PC 3，在体外。这三种限制抑制能量产生（ATP合成）并诱导活性氧（ROS）的产生。DUI 45中的Tyr/Phe或Met和PC 3中的Met的限制降低线粒体膜电位（Δ Psim）并诱导半胱天冬酶依赖性和非依赖性细胞凋亡。在DUI 45中，Tyr/Phe或Met限制降低Akt的活性、磷酸化Raf和凋亡诱导因子（AIF）的线粒体分布，并增加巴克的线粒体分布。线粒体BcI-XL在Tyr/Phe限制的细胞中增加，但在Met限制的细胞中减少。在Tyr/Phe或Met限制下，减少的线粒体Raf不妨碍巴克的促凋亡功能。Tyr/Phe限制也抑制BcI-2，Met限制抑制线粒体中的BcI-XL。这些综合作用破坏线粒体的完整性并诱导DU 145的凋亡。在PC 3中，Met限制诱导的细胞凋亡与Raf、BcI-2家族蛋白或AIF的细胞内分布改变无关。所有的氨基酸限制抑制Akt在该细胞系中的活性。我们的结论是，特定的氨基酸限制差异干扰Raf和Akt生存途径之间的稳态/平衡，并与Raf和Bcl-2家族蛋白在线粒体中的相互作用，以诱导DU 145和PC 3细胞的凋亡。
Relative specific amino acid dependency is one of the metabolic abnormalities of cancer cells, and restriction of specific amino acids induces apoptosis of Prostate cancer cells. This study shows that restriction of tyrosine and phenylalanine (Tyr/Phe), glutamine (GIn), or methionine (Met), modulates Raf and Akt survival pathways and affects the function of mitochondria in DUI 45 and PC3, in vitro. These three restrictions inhibit energy production (ATP synthesis) and induce generation of reactive oxygen species (ROS). Restriction of Tyr/Phe or Met in DUI 45 and Met in PC3 reduces mitochondrial membrane potential (Delta Psi m) and induces caspase-dependent and -independent apoptosis. In DUI 45, Tyr/Phe or Met restriction reduces activity of Akt, mitochondrial distribution of phosphorylated Raf and apoptosis inducing factor (AIF), and increases mitochondrial distribution of Bak. Mitochondrial BcI-XL is increased in Tyr/Phe-restricted but decreased in Met-restricted cells. Under Tyr/Phe or Met restriction, reduced mitochondrial Raf does not inactivate the pro-apoptotic function of Bak. Tyr/Phe restriction also inhibits BcI-2 and Met restriction inhibits BcI-XL in mitochondria. These comprehensive actions damage the integrity of the mitochondria and induce apoptosis of DU145. In PC3, apoptosis induced by Met restriction was not associated with alterations in intracellular distribution of Raf, BcI-2 family proteins, or AIF. All of the amino acid restrictions inhibited Akt activity in this cell line. We conclude that specific amino acid restriction differentially interferes with homeostasis/balance between the Raf and Akt survival pathways and with the interaction of Raf and BcI-2 family proteins in mitochondria to induce apoptosis of DU145 and PC3 cells.