Identification of potential inhibitors of tropomyosin receptor kinase B targeting CNS-related disorders and cancers

Hakami, Mohammed Ageeli; Alotaibi, Bader S.; Hazazi, Ali; Shafie, Alaa; Alsaiari, Ahad Amer; Ashour, Amal Adnan; Anjum, Farah

doi:10.1080/07391102.2023.2212786

Cited by 2 publications

(3 citation statements)

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“…TrkB is a significant suppression target in many cancer cells [ 92 – 95 ], as in many other conditions driven by excessive proliferation, such as endometriosis [ 96 ]. TrkB activation enhances the survival and proliferation of cancer stem-like cells as well as increasing metastasis, epithelial-mesenchymal transition (EMT), vascular invasion and poor prognosis [ 97 – 100 ].…”

Section: Cortisol Melatonin Trkb and Tumor Microenvironment Cellsmentioning

confidence: 99%

“…It is unknown as to whether NAS directly or indirectly modulates BAG-1 and GR site of translocation or whether it could do so differentially in different cell types/phenotypes via miRNA and/or lncRNA regulation. It is widely recognized that TrkB activation is a significant target in cancer treatment [ 92 , 93 ], with TrkB activation driving the proliferation and survival of cancer stem-like cells [ 36 , 146 ], with differential effects on immune cells, versus melatonin and GR, as indicated in Table 1 . Such data strongly indicates that an increase in the pineal NAS/melatonin ratio at night would have direct systemic effects on tumor pathogenesis and pathophysiology as well as indirect effects via the circadian regulation by NAS at TrkB of hypothalamic hormones.…”

Section: Hypothalamic Interactions Of Melatonin Gr and Trkb In Tumor ...mentioning

confidence: 99%

“…For example, melatonin increases mitophagy and PTEN-associated kinase 1 (PINK1)/parkin to suppress CD8 + T cell chemoattraction in "immune-mediated" conditions, such as Parkinson's disease [2,89], but suppresses mitophagy in cancer cells [90], whilst also derepressing CD8 + T cells [60]. However, melatonin generally has suppressive effects on pro-inflammatory responses by Th1 and Th17 cells, whilst potentiating Treg [91], in contrast to GR effects [81,82]. Importantly, the direct optimizing effects of melatonin on NK cells and CD8 + T cells [86,87], as well as indirect effects via altering tumor fluxes to cytolytic cells [60] are in sharp contrast to GR effects, as are melatonin effects in cancer cells.…”

Section: Cortisol Melatonin Trkb and Tumor Microenvironment Cellsmentioning

confidence: 99%

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Melatonin, BAG-1 and cortisol circadian interactions in tumor pathogenesis and patterned immune responses

Anderson

2023

Exploration of Targeted Anti-Tumor Therapy

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A dysregulated circadian rhythm is significantly associated with cancer risk, as is aging. Both aging and circadian dysregulation show suppressed pineal melatonin, which is indicated in many studies to be linked to cancer risk and progression. Another independently investigated aspect of the circadian rhythm is the cortisol awakening response (CAR), which is linked to stress-associated hypothalamus-pituitary-adrenal (HPA) axis activation. CAR and HPA axis activity are primarily mediated via activation of the glucocorticoid receptor (GR), which drives patterned gene expression via binding to the promotors of glucocorticoid response element (GRE)-expressing genes. Recent data shows that the GR can be prevented from nuclear translocation by the B cell lymphoma-2 (Bcl-2)-associated athanogene 1 (BAG-1), which translocates the GR to mitochondria, where it can have diverse effects. Melatonin also suppresses GR nuclear translocation by maintaining the GR in a complex with heat shock protein 90 (Hsp90). Melatonin, directly and/or epigenetically, can upregulate BAG-1, suggesting that the dramatic 10-fold decrease in pineal melatonin from adolescence to the ninth decade of life will attenuate the capacity of night-time melatonin to modulate the effects of the early morning CAR. The interactions of pineal melatonin/BAG-1/Hsp90 with the CAR are proposed to underpin how aging and circadian dysregulation are associated with cancer risk. This may be mediated via differential effects of melatonin/BAG-1/Hsp90/GR in different cells of microenvironments across the body, from which tumors emerge. This provides a model of cancer pathogenesis that better integrates previously disparate bodies of data, including how immune cells are regulated by cancer cells in the tumor microenvironment, at least partly via the cancer cell regulation of the tryptophan-melatonin pathway. This has a number of future research and treatment implications.

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Section: Cortisol Melatonin Trkb and Tumor Microenvironment Cellsmentioning

confidence: 99%

Section: Hypothalamic Interactions Of Melatonin Gr and Trkb In Tumor ...mentioning

confidence: 99%

Section: Cortisol Melatonin Trkb and Tumor Microenvironment Cellsmentioning

confidence: 99%

See 1 more Smart Citation

Melatonin, BAG-1 and cortisol circadian interactions in tumor pathogenesis and patterned immune responses

Anderson

2023

Exploration of Targeted Anti-Tumor Therapy

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Causal role of myeloid cells in Parkinson’s disease: Mendelian randomization study

Quan,

Qin,

et al. 2024

Inflamm. Res.

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Identification of potential inhibitors of tropomyosin receptor kinase B targeting CNS-related disorders and cancers

Cited by 2 publications

References 56 publications

Melatonin, BAG-1 and cortisol circadian interactions in tumor pathogenesis and patterned immune responses

Melatonin, BAG-1 and cortisol circadian interactions in tumor pathogenesis and patterned immune responses

Causal role of myeloid cells in Parkinson’s disease: Mendelian randomization study

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