Caino M Cecilia, Altieri Dario C
a Prostate Cancer Discovery and Development Program, Tumor Microenvironment and Metastasis Program, The Wistar Institute ; Philadelphia , PA USA.
Cell Cycle. 2015;14(20):3242-7. doi: 10.1080/15384101.2015.1084448.
Mitochondria are organelles that orchestrate a plethora of fundamental cellular functions that have been associated with various steps of tumor progression. However, we currently lack a mechanistic understanding of how mitochondrial dynamics, which reflects the organelles' exquisite heterogeneity in shape and spatial distribution, affects tumorigenesis. In a recent study, we uncovered a surprising new role of mitochondrial dynamics in response to PI3K therapy. We found that re-activation of Akt/mTOR signaling in tumor cells exposed to small molecule PI3K antagonists currently in the clinic triggered the transport of energetically active, elongated mitochondria to the cortical cytoskeleton of tumor cells. In turn, these repositioned mitochondria supported increased lamellipodia dynamics, faster turnover of focal adhesion complexes, heightened velocity and distance of random cell migration and increased tumor cell invasion. In this Extra View, we discuss the mechanistic basis of this paradoxical response to PI3K antagonists and propose possible strategies to disable mitochondrial adaptation.
线粒体是协调众多基本细胞功能的细胞器，这些功能与肿瘤进展的各个阶段相关。然而，目前我们对线粒体动力学（反映细胞器在形状和空间分布上的精细异质性）如何影响肿瘤发生缺乏机制上的理解。在最近的一项研究中，我们发现了线粒体动力学在对PI3K治疗的反应中的一个惊人新作用。我们发现，在暴露于目前临床使用的小分子PI3K拮抗剂的肿瘤细胞中，Akt/mTOR信号的重新激活触发了能量活跃的细长线粒体向肿瘤细胞皮质细胞骨架的转运。反过来，这些重新定位的线粒体支持了片状伪足动力学的增加、粘着斑复合物的更快周转、随机细胞迁移的速度和距离的提高以及肿瘤细胞侵袭的增加。在这篇扩展观点文章中，我们讨论了对PI3K拮抗剂这种矛盾反应的机制基础，并提出了使线粒体适应失效的可能策略。
