Crosstalk from non-cancerous mitochondria can inhibit tumor properties of metastatic cells by suppressing oncogenic pathways.
Crosstalk from non-cancerous mitochondria can inhibit tumor properties of metastatic cells by suppressing oncogenic pathways.
复制标题
DOI：
10.1371/journal.pone.0061747
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Wong LJ
中科院分区：
文献类型：
--
作者：
Kaipparettu BA;Ma Y;Park JH;Lee TL;Zhang Y;Yotnda P;Creighton CJ;Chan WY;Wong LJ
线粒体-核的相互作用和线粒体的逆行调节可以在细胞特性中发挥重要作用。跨线粒体胞质杂交系统(Cybrids)是研究特定核背景下线粒体变化的特定效应的极好工具。使用Cybrid模型的大多数研究集中于特定线粒体DNA变异在线粒体功能或肿瘤特性中的意义。然而，这些变异大多是良性的多态，没有已知的功能意义。从纠正癌细胞线粒体缺陷和建立线粒体作为潜在的抗癌药物靶点的目标出发，了解在癌症核背景下功能线粒体在逆转肿瘤发生特性中的作用是非常重要的。在这里，我们分析了引入非癌线粒体可能逆转高转移细胞系的致癌特性。将侵袭性骨肉瘤细胞系TK-ρ0细胞的线粒体与乳腺良性上皮细胞系MCF10A、中等转移性乳腺癌细胞系MDAMB-468和143B细胞的线粒体融合，构建胞质杂交体。尽管线粒体供体细胞具有统一的癌变核背景，但与具有癌变线粒体的胞体相比，具有良性线粒体的胞体表现出更高的线粒体功能特性，包括增加ATP合成、氧耗和呼吸链活性。有趣的是，良性线粒体可以逆转143B TK细胞的不同致癌特性，包括细胞增殖、低氧条件下的生存能力、抗凋亡特性、抗癌药物耐药性、软琼脂侵袭和集落形成以及裸鼠体内肿瘤生长。微阵列分析表明，在含有癌症线粒体的胞质中观察到的几条致癌途径在含有非癌线粒体的胞质中受到抑制。这些结果提示了线粒体-核串扰对致癌的关键调控，并强调纠正线粒体的功能特性是癌症治疗的一个有希望的靶点。
Mitochondrial-nucleus cross talks and mitochondrial retrograde regulation can play a significant role in cellular properties. Transmitochondrial cybrid systems (cybrids) are an excellent tool to study specific effects of altered mitochondria under a defined nuclear background. The majority of the studies using the cybrid model focused on the significance of specific mitochondrial DNA variations in mitochondrial function or tumor properties. However, most of these variants are benign polymorphisms without known functional significance. From an objective of rectifying mitochondrial defects in cancer cells and to establish mitochondria as a potential anticancer drug target, understanding the role of functional mitochondria in reversing oncogenic properties under a cancer nuclear background is very important. Here we analyzed the potential reversal of oncogenic properties of a highly metastatic cell line with the introduction of non-cancerous mitochondria. Cybrids were established by fusing the mitochondria DNA depleted 143B TK- ρ0 cells from an aggressive osteosarcoma cell line with mitochondria from benign breast epithelial cell line MCF10A, moderately metastatic breast cancer cell line MDA-MB-468 and 143B cells. In spite of the uniform cancerous nuclear background, as observed with the mitochondria donor cells, cybrids with benign mitochondria showed high mitochondrial functional properties including increased ATP synthesis, oxygen consumption and respiratory chain activities compared to cybrids with cancerous mitochondria. Interestingly, benign mitochondria could reverse different oncogenic characteristics of 143B TK- cell including cell proliferation, viability under hypoxic condition, anti-apoptotic properties, resistance to anti-cancer drug, invasion, and colony formation in soft agar, and in vivo tumor growth in nude mice. Microarray analysis suggested that several oncogenic pathways observed in cybrids with cancer mitochondria are inhibited in cybrids with non-cancerous mitochondria. These results suggest the critical oncogenic regulation by mitochondrial-nuclear cross talk and highlights rectifying mitochondrial functional properties as a promising target in cancer therapy.
登录
查看更多内容
多种致癌途径特征显示人类前列腺肿瘤中的坐标表达模式。
影响因子：
3.7
作者：
Creighton, Chad J.
通讯作者：
Creighton, Chad J.
影响因子：
45.3
作者：
Davids, Matthew S.;Letai, Anthony
通讯作者：
Letai, Anthony
影响因子：
56.9
作者：
Ishikawa, Kaori;Takenaga, Keizo;Hayashi, Jun-Ichi
通讯作者：
Hayashi, Jun-Ichi
影响因子：
16.2
作者：
ANKARCRONA, M;DYPBUKT, JM;NICOTERA, P
通讯作者：
NICOTERA, P
影响因子：
4.3
作者：
Ma, Yewei;Bai, Ren-Kui;Wong, Lee-Jun C.
通讯作者：
Wong, Lee-Jun C.