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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.
Highlights
The symptom of prion protein infection was first described in 1732 when Merino sheep scraped pathologically against fences [1], but the term prion (PRoteinaceous Infective ONly particle) was not coined until 1982 by Prusiner who defined prions in 1998 as heritable, infectious, proteinaceous particles that are converted from the normal, cellular form (PrPC) into the pathogenic form (PrPSc) that associates with amyloid plaques [2,3]
Quantitative transcriptomics analysis (RNA-Seq) of 27 different tissues obtained from 95 human individuals [26] found the prion gene prion protein gene (PRNP) to be ubiquitously expressed in all 27 human tissues examined in addition to mitochondria, with the highest expressions found in the brain, followed by the ovary, prostate, heart, gallbladder, endometrium, adrenal, urinary bladder, thyroid, testis, skin, esophagus, and lung [27]
Since prion targeting of lipid rafts [272,325,326] can affect membrane signaling [327,328] and lipid composition [329], the role of melatonin in the prevention of lipid peroxidation, modification of lipid hydrocarbon chain to promote phase separation in ternary membrane models [330,331], stabilizing lipid liquid ordered (Lo) to liquid disordered (Ld) phase separation over a range of temperatures [332], and displacing cholesterol in competitive binding to lipid molecules [330] provides additional insight into the complex relationship between melatonin and prion physiological and potential pathological conversion mediated by phase separation and associated processes
Summary
The symptom of prion protein infection was first described in 1732 when Merino sheep scraped pathologically against fences [1], but the term prion (PRoteinaceous Infective ONly particle) was not coined until 1982 by Prusiner who defined prions in 1998 as heritable, infectious, proteinaceous particles that are converted from the normal, cellular form (PrPC) into the pathogenic form (PrPSc) that associates with amyloid plaques [2,3]. The fact that PrPC enhances clinical resistance to cisplatin in colorectal cancer cell [88] and increases invasiveness and resistance to doxorubicininduced apoptosis in LS 174T colon cancer cells [89] supports the theory that PrPC serves important physiological functions [5] including antioxidant protection [90]. When used in combination with anti-cancer drugs such as oxaliplatin and 5-fluorouracil (5-FU), melatonin becomes even more effective in inducing apoptosis and senescence in 5-FU-resistant colon stem cells and oxaliplatin-resistant colorectal cancer cells by suppressing PrPC expression [115,116]. Using 2 mM melatonin (2000-fold increase) in LPSstimulated prostate cancer cells inhibited migration and invasion [119]; the addition of 1 mM melatonin inhibited cellular prion protein expression to promote apoptosis via superoxide-mediated oxidative stress in colorectal cancer cells [114]. Living organisms may have always relied upon melatonin to effectively modulate prion propagation using unique features including the regulation of liquid–liquid phase separation [125]
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