Department of Anatomy, Institute of Biosciences of Botucatu, UNESP, São Paulo State University, P.O Box: 18618-689, R. Prof. Dr. Antônio Celso Wagner Zanin, 250, Rubião Júnior, Botucatu, SP, Brazil.
Department of Biology and Technology, UENP/CLM, Universidade Estadual do Norte do Paraná, Bandeirantes, Paraná, Brazil.
Cell Mol Life Sci. 2019 Mar;76(5):837-863. doi: 10.1007/s00018-018-2963-0. Epub 2018 Nov 14.
Cancers of the reproductive organs have a strong association with mitochondrial defects, and a deeper understanding of the role of this organelle in preneoplastic-neoplastic changes is important to determine the appropriate therapeutic intervention. Mitochondria are involved in events during cancer development, including metabolic and oxidative status, acquisition of metastatic potential, resistance to chemotherapy, apoptosis, and others. Because of their origin from melatonin-producing bacteria, mitochondria are speculated to produce melatonin and its derivatives at high levels; in addition, exogenously administered melatonin accumulates in the mitochondria against a concentration gradient. Melatonin is transported into tumor cell by GLUT/SLC2A and/or by the PEPT1/2 transporters, and plays beneficial roles in mitochondrial homeostasis, such as influencing oxidative phosphorylation and electron flux, ATP synthesis, bioenergetics, calcium influx, and mitochondrial permeability transition pore. Moreover, melatonin promotes mitochondrial homeostasis by regulating nuclear DNA and mtDNA transcriptional activities. This review focuses on the main functions of melatonin on mitochondrial processes, and reviews from a mechanistic standpoint, how mitochondrial crosstalk evolved in ovarian, endometrial, cervical, breast, and prostate cancers relative to melatonin's known actions. We put emphasis on signaling pathways whereby melatonin interferes within cancer-cell mitochondria after its administration. Depending on subtype and intratumor metabolic heterogeneity, melatonin seems to be helpful in promoting apoptosis, anti-proliferation, pro-oxidation, metabolic shifting, inhibiting neovasculogenesis and controlling inflammation, and restoration of chemosensitivity. This results in attenuation of development, progression, and metastatic potential of reproductive cancers, in addition to lowering the risk of recurrence and improving the life quality of patients.
生殖器官癌症与线粒体缺陷密切相关，深入了解细胞器在癌前-肿瘤变化中的作用对于确定适当的治疗干预措施非常重要。线粒体参与癌症发展过程中的事件，包括代谢和氧化状态、获得转移潜能、对化疗的耐药性、细胞凋亡等。由于它们起源于产生褪黑素的细菌，因此推测线粒体可以高水平地产生褪黑素及其衍生物；此外，外源性给予的褪黑素可以在浓度梯度的作用下积累在线粒体中。褪黑素通过 GLUT/SLC2A 和/或 PEPT1/2 转运体进入肿瘤细胞，并在维持线粒体稳态方面发挥有益作用，如影响氧化磷酸化和电子流、ATP 合成、生物能学、钙内流和线粒体通透性转换孔。此外，褪黑素通过调节核 DNA 和 mtDNA 转录活性来促进线粒体稳态。本综述重点关注褪黑素对线粒体过程的主要功能，并从机制角度综述了相对于褪黑素已知作用，卵巢癌、子宫内膜癌、宫颈癌、乳腺癌和前列腺癌中线粒体串扰是如何进化的。我们强调了信号通路，即在褪黑素给药后，其如何干扰癌细胞线粒体。根据亚型和肿瘤内代谢异质性，褪黑素似乎有助于促进细胞凋亡、抗增殖、促氧化、代谢转变、抑制新生血管生成和控制炎症，并恢复化疗敏感性。这不仅可以降低生殖系统癌症的发展、进展和转移潜能的风险，还可以降低复发风险并提高患者的生活质量。
