CRG-Centre for Genomic Regulation, 08003 Barcelona, Spain.
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy.
Biomolecules. 2020 Jan 14;10(1):135. doi: 10.3390/biom10010135.
Metabolic reprogramming, carried out by cancer cells to rapidly adapt to stress such as hypoxia and limited nutrient conditions, is an emerging concepts in tumor biology, and is now recognized as one of the hallmarks of cancer. In contrast with conventional views, based on the classical Warburg effect, these metabolic alterations require fully functional mitochondria and finely-tuned regulations of their activity. In turn, the reciprocal regulation of the metabolic adaptations of cancer cells and the microenvironment critically influence disease progression and response to therapy. This is also realized through the function of specific stress-adaptive proteins, which are able to relieve oxidative stress, inhibit apoptosis, and facilitate the switch between metabolic pathways. Among these, the molecular chaperone tumor necrosis factor receptor associated protein 1 (TRAP1), the most abundant heat shock protein 90 (HSP90) family member in mitochondria, is particularly relevant because of its role as an oncogene or a tumor suppressor, depending on the metabolic features of the specific tumor. This review highlights the interplay between metabolic reprogramming and cancer progression, and the role of mitochondrial activity and oxidative stress in this setting, examining the possibility of targeting pathways of energy metabolism as a therapeutic strategy to overcome drug resistance, with particular emphasis on natural compounds and inhibitors of mitochondrial HSP90s.
代谢重编程是癌细胞为了快速适应缺氧和营养有限等应激而进行的一种新兴概念，现已被认为是肿瘤生物学的特征之一。与基于经典沃伯格效应的传统观点相反，这些代谢改变需要功能齐全的线粒体和精细调节其活性。反过来，癌细胞代谢适应和微环境的相互调节对疾病进展和治疗反应有至关重要的影响。这也通过特定应激适应蛋白的功能来实现，这些蛋白能够缓解氧化应激、抑制细胞凋亡，并促进代谢途径之间的转换。其中，分子伴侣肿瘤坏死因子受体相关蛋白 1（TRAP1）是线粒体中最丰富的热休克蛋白 90（HSP90）家族成员，由于其作为癌基因或肿瘤抑制因子的作用而特别相关，具体取决于特定肿瘤的代谢特征。这篇综述强调了代谢重编程与癌症进展之间的相互作用，以及线粒体活性和氧化应激在这一环境中的作用，探讨了将能量代谢途径作为一种治疗策略来克服耐药性的可能性，特别强调了天然化合物和线粒体 HSP90 的抑制剂。
