Independent Researcher, Marble Falls, TX 78654, USA.
Department of Cellular and Structural Biology, UT Health San Antonio, San Antonio, TX 78229, USA.
Molecules. 2022 Jan 21;27(3):705. doi: 10.3390/molecules27030705.
The unique ability to adapt and thrive in inhospitable, stressful tumor microenvironments (TME) also renders cancer cells resistant to traditional chemotherapeutic treatments and/or novel pharmaceuticals. Cancer cells exhibit extensive metabolic alterations involving hypoxia, accelerated glycolysis, oxidative stress, and increased extracellular ATP that may activate ancient, conserved prion adaptive response strategies that exacerbate multidrug resistance (MDR) by exploiting cellular stress to increase cancer metastatic potential and stemness, balance proliferation and differentiation, and amplify resistance to apoptosis. The regulation of prions in MDR is further complicated by important, putative physiological functions of ligand-binding and signal transduction. Melatonin is capable of both enhancing physiological functions and inhibiting oncogenic properties of prion proteins. Through regulation of phase separation of the prion N-terminal domain which targets and interacts with lipid rafts, melatonin may prevent conformational changes that can result in aggregation and/or conversion to pathological, infectious isoforms. As a cancer therapy adjuvant, melatonin could modulate TME oxidative stress levels and hypoxia, reverse pH gradient changes, reduce lipid peroxidation, and protect lipid raft compositions to suppress prion-mediated, non-Mendelian, heritable, but often reversible epigenetic adaptations that facilitate cancer heterogeneity, stemness, metastasis, and drug resistance. This review examines some of the mechanisms that may balance physiological and pathological effects of prions and prion-like proteins achieved through the synergistic use of melatonin to ameliorate MDR, which remains a challenge in cancer treatment.
癌症细胞在不利于生存的、有压力的肿瘤微环境（TME）中具有独特的适应和茁壮成长的能力，这也使其对传统的化疗治疗和/或新型药物具有耐药性。癌症细胞表现出广泛的代谢改变，涉及缺氧、加速糖酵解、氧化应激和增加细胞外 ATP，这些改变可能会激活古老的、保守的朊病毒适应性反应策略，通过利用细胞应激来增加癌症的转移潜力和干性，平衡增殖和分化，并放大对细胞凋亡的抵抗，从而加剧多药耐药性（MDR）。配体结合和信号转导的重要假定生理功能进一步复杂化了 MDR 中朊病毒的调节。褪黑素既能增强朊病毒蛋白的生理功能，又能抑制其致癌特性。通过调节朊病毒 N 端结构域的相分离，该结构域靶向并与脂筏相互作用，褪黑素可以防止导致聚集和/或转化为病理性、传染性异构体的构象变化。作为癌症治疗的辅助剂，褪黑素可以调节 TME 中的氧化应激水平和缺氧，逆转 pH 梯度变化，减少脂质过氧化，并保护脂筏组成，以抑制朊病毒介导的、非孟德尔的、可遗传但通常可逆转的表观遗传适应，从而促进癌症异质性、干性、转移和耐药性。这篇综述检查了一些可能平衡朊病毒和朊病毒样蛋白的生理和病理效应的机制，这些机制是通过协同使用褪黑素来改善 MDR 实现的，MDR 仍然是癌症治疗中的一个挑战。
