Melatonin reduces proliferation and promotes apoptosis of bladder cancer cells by suppressing O‐GlcNAcylation of cyclin‐dependent‐like kinase 5

Wu, Jinpeng; Tan, Zengqi; Li, Hongjiao; Lin, Meixuan; Jiang, Yazhuo; Liang, Liang; Ma, Qilong; Gou, Junjie; Ning, Lulu; Li, Xiang; Guan, Feng

doi:10.1111/jpi.12765

Cited by 33 publications

(24 citation statements)

References 56 publications

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“…However, melatonin (7) has been found to inhibit the proliferation of bladder cancer cells and induces apoptosis via blocking O-GlcNAcylation of CDK5 (Figure 1). 73 CDK1/2/5 kinase activity is significant for interferon γ (IFNG)-mediated tumor immune evasion. Use of the CDK1/2/5 inhibitor dinaciclib (1) induced apoptosis of tumor cells and stimulated CD8+ T cell-dependent antitumor immunity in pancreatic cancer.…”

Section: Cdk5 Functions In Cancermentioning

confidence: 99%

“…It is anticipated that these advancements will facilitate the clinical translation of these inhibitors in the future. Inhibition of CDK5 has been shown to mediate the cell death of tumor-initiating cells (TICs), 148 promote the differentiation of ductal progenitors into β-cell, 149 promote the differentiation of osteoblasts and fracture healing, 150 reduce the proliferation of cancer cells and promote apoptosis, 73 and others. Despite the potential benefits of CDK5-selective inhibitors, progress in their development has been hindered at the primary stage.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

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Novel Medicinal Chemistry Strategies Targeting CDK5 for Drug Discovery

Tang

Lin

et al. 2023

J. Med. Chem.

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Cyclin-dependent kinase 5 (CDK5) protein plays an important role not only in the central nervous system but also in the periphery, including immune response, regulation of insulin secretion, and cancer development and progression. Consequently, targeting the CDK5 protein is a potential strategy for the treatment of many diseases, especially cancer and neurodegenerative diseases. To date, numerous pan-CDK inhibitors have entered clinical trials. Nevertheless, limited clinical efficacy and severe adverse effects have prompted the application of new techniques to optimize clinical efficacy and minimize adverse events. In this Perspective, we highlight the protein properties, biofunctions, relevant signaling pathways, and associations with cancer development and proliferation of CDK5, and analyze the clinical status of pan-CDK inhibitors and the preclinical status of CDK5-specific inhibitors. In addition, CDK5-selective inhibitors, protein–protein interaction inhibitors, proteolytic-targeting chimera (PROTAC) degraders, and dual-target CDK5 inhibitors are discussed.

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Section: Cdk5 Functions In Cancermentioning

confidence: 99%

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Novel Medicinal Chemistry Strategies Targeting CDK5 for Drug Discovery

Tang

Lin

et al. 2023

J. Med. Chem.

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“…For instance, in gastric cancer cells, melatonin induced apoptosis by downregulating the mouse double minute 2 homolog (MDM2) [ 28 ]. It also induced apoptosis by suppressing o-GlcNAcylation of cyclin-dependent-like kinase 5 (CDK5) in bladder cancer cells [ 29 ]. In a mouse ovarian tumor xenograft model, melatonin prompted apoptosis by stabilizing Bim via Sp1-mediated tumor domain-containing protein 1 (OTUD1) upregulation [ 30 ].…”

Section: Anticancer Effect Of Melatoninmentioning

confidence: 99%

Use of Melatonin in Cancer Treatment: Where Are We?

Wang

Choi

2022

IJMS

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Cancer represents a large group of diseases accounting for nearly 10 million deaths each year. Various treatment strategies, including surgical resection combined with chemotherapy, radiotherapy, and immunotherapy, have been applied for cancer treatment. However, the outcomes remain largely unsatisfying. Melatonin, as an endogenous hormone, is associated with the circadian rhythm moderation. Many physiological functions of melatonin besides sleep–wake cycle control have been identified, such as antioxidant, immunomodulation, and anti-inflammation. In recent years, an increasing number of studies have described the anticancer effects of melatonin. This has drawn our attention to the potential usage of melatonin for cancer treatment in the clinical setting, although huge obstacles still exist before its wide clinical administration is accepted. The exact mechanisms behind its anticancer effects remain unclear, and the specific characters impede its in vivo investigation. In this review, we will summarize the latest advances in melatonin studies, including its chemical properties, the possible mechanisms for its anticancer effects, and the ongoing clinical trails. Importantly, challenges for the clinical application of melatonin will be discussed, accompanied with our perspectives on its future development. Finally, obstacles and perspectives of using melatonin for cancer treatment will be proposed. The present article will provide a comprehensive foundation for applying melatonin as a preventive and therapeutic agent for cancer treatment.

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“…Melatonin has previously been shown to inhibit the growth of BC (Reiter et al 2017 ). Wu et al ( 2021 ) further revealed the anti-prostate cancer mechanism of melatonin: Melatonin inhibits O -GlcNAcylation of cyclin-dependent kinase 5 (CDK5) at Thr246, thus promoting its degradation, and inhibiting the tumor-promoting effect of CDK5 on BC cells.…”

Section: O -Glcnac and Cancermentioning

confidence: 99%

O-GlcNAcylation: an important post-translational modification and a potential therapeutic target for cancer therapy

Zhang

Liang

et al. 2022

Mol Med

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O-linked β-d-N-acetylglucosamine (O-GlcNAc) is an important post-translational modification of serine or threonine residues on thousands of proteins in the nucleus and cytoplasm of all animals and plants. In eukaryotes, only two conserved enzymes are involved in this process. O-GlcNAc transferase is responsible for adding O-GlcNAc to proteins, while O-GlcNAcase is responsible for removing it. Aberrant O-GlcNAcylation is associated with a variety of human diseases, such as diabetes, cancer, neurodegenerative diseases, and cardiovascular diseases. Numerous studies have confirmed that O-GlcNAcylation is involved in the occurrence and progression of cancers in multiple systems throughout the body. It is also involved in regulating multiple cancer hallmarks, such as metabolic reprogramming, proliferation, invasion, metastasis, and angiogenesis. In this review, we first describe the process of O-GlcNAcylation and the structure and function of O-GlcNAc cycling enzymes. In addition, we detail the occurrence of O-GlcNAc in various cancers and the role it plays. Finally, we discuss the potential of O-GlcNAc as a promising biomarker and novel therapeutic target for cancer diagnosis, treatment, and prognosis.

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Melatonin reduces proliferation and promotes apoptosis of bladder cancer cells by suppressing O‐GlcNAcylation of cyclin‐dependent‐like kinase 5

Cited by 33 publications

References 56 publications

Novel Medicinal Chemistry Strategies Targeting CDK5 for Drug Discovery

Novel Medicinal Chemistry Strategies Targeting CDK5 for Drug Discovery

Use of Melatonin in Cancer Treatment: Where Are We?

O-GlcNAcylation: an important post-translational modification and a potential therapeutic target for cancer therapy

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