Melatonin: Regulation of Prion Protein Phase Separation in Cancer Multidrug Resistance

Abstract

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.

Liquid–liquid phase separation in tumor biology

“… 296 Moreover, researchers have also analogously demonstrated that the anticancer adjuvant melatonin is capable of inhibiting the intrinsically disordered N-terminal region of prion-mediated phase separation in cancer, which results in the amelioration of multidrug resistance. 297 …”

Understanding the Mechanism of Action of Melatonin, Which Induces ROS Production in Cancer Cells

“…Some studies have shown that melatonin reduces PrPC levels, leading to a decrease in antioxidant defenses in cancer cells [ 78 ]. Lee et al [ 79 ] reported that PrPC levels increased in human oxaliplatin-resistant cell lines (SNU-C5/Oxal-R), resulting in an increased antioxidant effect through an increase in SOD and catalase activity.…”

Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19

“…While the in vitro treatment of mouse spermatogonial stem cells (SSCs) with 10 µM Cr (VI) produced a clear loss of m 6 A modification after 1 h, in addition to a marked reduction in METTL3 expression and m 6 A modifications of mitochondrial fusion genes after 4 h of exposure, pretreatment with 50 µM melatonin not only restored METTL3 levels but also attenuated suppression of m 6 A modifications in Cr (VI)-treated ESCs compared to controls [872] (Table 2). Ultimately, melatonin is a "broad-based metabolic buffer" [415] that is used by living organisms in all three domains of life to reduce exogenous and endogenous stress by maintaining redox homeostasis in antioxidant-and prooxidant-dependent and -independent means [873][874][875][876][877][878]. In general, the knockdown of METTL3, METTL14, and ALKBH5 are associated with reduced SARS-CoV-2 viral replication, but knocking down YTHDF2 and FTO has the opposite effect of increasing viral replication during SARS-CoV-2 infection (Section 7.5, Table 1).…”

“…Melatonin is an osmoregulator with pleiotropic effects on plasma sodium concentration in animal models [ 409 , 410 ]. This ancient molecule is indispensable in maintaining ion homeostasis in plants [ 411 , 412 , 413 ], and its comprehensive role as a “broad-based metabolic buffer” includes rhythmic circadian modulation of the Na + /K + -ATPase as well as the Na + /H + exchanger ion-transport activities in human erythrocytes via antioxidant-dependent and -independent mechanisms [ 414 , 415 ]. Both Na + /K + -ATPase and Na + /H + can influence transmembrane chemical gradients [ 416 , 417 ], as well as cytosolic pH and ionic balance [ 418 , 419 , 420 ].…”

“…The assembly of SGs is one of the major mechanisms used by cancer cells to adapt and survive under inhospitable, toxic microenvironments [ 608 , 609 ], as well as developing resistance to anticancer therapies [ 610 ]. Melatonin is known for its anticancer features, acting as a “broad-based metabolic buffer” to tune the cancer microenvironment [ 415 ]. Consequently, the inhibition of AKT to activate GSK-3β in melanoma cells may result in the phosphorylation of Gle1A, which subsequently disassembled SGs, explaining the potential mechanism for the reduction of cell viability to ~50% observed at 72 h [ 603 ].…”