Role of TRPM2 in brain tumours and potential as a drug target

Ji, Delphine; Luo, Zhi‐Chao; Ovcjak, Andrea; Alanazi, Rahmah; Bao, Meihua; Feng, Zhong‐Ping; Sun, Hong‐Shuo

doi:10.1038/s41401-021-00679-4

Cited by 12 publications

(6 citation statements)

References 148 publications

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“…Ji D et al analyzed TRPM2 as an ion channel in terms of oxidative stress and reported that it was essential for cellular function and played an important role in oxidative stress and inflammation; they summarized the current understanding of TRPM2 in brain tumors and reviewed potential pharmacotherapeutic roles of TRPM2. The importance of TRPM2, as a potential therapeutic target for brain tumors, in ion channels and pharmacology was reported in a previous study [46]. In our study, the differential expression of TRPM2 and TRPM4 in tumor and para-carcinoma tissues was extremely clear (Figure S1), indicating the important role of these TRP family genes in the tumorigenicity in various cancers.…”

Section: Discussionsupporting

confidence: 79%

Pan-Cancer Analysis of the TRP Family, Especially TRPV4 and TRPC4, and Its Expression Correlated with Prognosis, Tumor Microenvironment, and Treatment Sensitivity

et al. 2023

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Background: Transient receptor potential (TRP) channels are involved in various physiological, pathological, and tumorigenesis-related processes. However, only a few studies have comprehensively analyzed TRP family members and their association with prognosis and tumor microenvironment (TME) in various cancers. Thus, in this study, we focused on TRP channels in pan-cancer and screened two typical TRP channels, TRPV4 and TRPC4, as examples. Methods: Based on the latest public databases, we evaluated the expression level and prognostic value of TRP family genes in pan-cancer tissues via various bioinformatic analytical methods, and investigated the relationship between the expression of TRP family genes with TME, stemness score, immune subtype, drug sensitivity, and immunotherapy outcome in pan-cancer tissues. Results: Pan-cancer analysis revealed that the TRP family genes were differentially expressed in tumor and para-carcinoma tissues. A significant correlation existed between the expression of TRP family genes and prognosis. The expression of TRP family genes was significantly correlated with stromal, immune, RNA stemness, and DNA stemness scores in pan-cancer tissues. Our results indicated that the expression of TRP family genes correlated with the sensitivity to various drugs including PLX-4720, SB-590885, and HYPOTHEMYCIN, immunotherapy outcome, and immune-activation-related genes. Immunohistochemical analysis revealed significant differential expression of TRPV4 in bladder and para-carcinoma tissues. Conclusions: Our study elucidated the possible role of TRP family genes in cancer progression and provided insights for further studies on TRP family genes as potential pan-cancer targets to develop diagnostic and therapeutic strategies.

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Section: Discussionsupporting

confidence: 79%

Pan-Cancer Analysis of the TRP Family, Especially TRPV4 and TRPC4, and Its Expression Correlated with Prognosis, Tumor Microenvironment, and Treatment Sensitivity

et al. 2023

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“…Consequently, although the various neurological diseases discussed here are different (i.e., PD vs. AD), some of the underlying mechanisms of cell death or dysfunction are similar, with ADPR acting on the NUDT9-H domain of TRPM2 and initiating Ca 2+ influx into the cytosol [10] . Furthermore, because TRPM2 is highly expressed in the brain in multiple cell types, inhibition of TRPM2 has the potential to modulate multiple pathways contributing to disease.…”

Section: Discussionmentioning

confidence: 99%

“…Modulation of TRPM2 has the potential to prevent apoptosis, minimize BBB leakage, and reduce the inflammatory response. Activated in response to oxidative stress and reactive oxygen species (ROS), which are common among different diseases, TRPM2 is involved in many neurological disorders, such as Parkinson's disease (PD), AD, ischemia, brain tumors, and aging [9,10] . TRPM2 is also implicated in the evolution and development of neuropsychiatric disorders.…”

Section: Introductionmentioning

confidence: 99%

Transient receptor potential melastatin 2 channels in neurological disorders: Mechanisms and animal models

Steinman¹,

Ovcjak²,

Luo³

et al. 2022

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Transient receptor potential melastatin 2 (TRPM2) is a calcium-permeable ion channel implicated in neurodegenerative disorders and conditions. It is activated in response to reactive oxygen species (ROS) and thereby alters Ca2+ homeostasis and initiates pathways that lead to apoptosis and cell dysfunction. This review summarizes the current role of TRPM2 in neurological disorders, including Parkinson’s disease, Alzheimer’s disease, ischemia, traumatic brain injury, and depressive disorders (bipolar disease and depression). It describes the distribution and function of the TRPM2 channel across the brain and highlights common mechanisms between diseases. Specific animal and cell culture studies using TRPM2 inhibitors or genetic knockouts are discussed, including strategies to reduce the effect of ROS in disease through TRPM2 inhibition.

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“…The present study identified new CXCL16-producing machinery in a TRPM2 autophagy-dependent manner in stressed keratinocytes, suggesting that TRPM2 serves an important role in the response to oxidative stress that elicits an immune response. In other cases, TRPM2 responds to oxidative injury and stimulates downstream TRPM2-hindered autophagy elevates CXCL16 449 signals, such as c-Jun N-terminal kinase and NF-κB [55]. We previously showed that TRPM2 activates nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome under oxidative stress in keratinocytes [5].…”

Section: P Kang Y Wang Et Almentioning

confidence: 99%

TRPM2‐dependent autophagy inhibition exacerbates oxidative stress‐induced CXCL16 secretion by keratinocytes in vitiligo

Kang,

Wang,

Chen

et al. 2024

The Journal of Pathology

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Vitiligo is a depigmented skin disease due to the destruction of melanocytes. Under oxidative stress, keratinocyte‐derived chemokine C‐X‐C motif ligand 16 (CXCL16) plays a critical role in recruiting CD8+ T cells, which kill melanocytes. Autophagy serves as a protective cell survival mechanism and impairment of autophagy has been linked to increased secretion of the proinflammatory cytokines. However, the role of autophagy in the secretion of CXCL16 under oxidative stress has not been investigated. Herein, we initially found that autophagy was suppressed in both keratinocytes of vitiligo lesions and keratinocytes exposed to oxidative stress in vitro. Autophagy inhibition also promoted CXCL16 secretion. Furthermore, upregulated transient receptor potential cation channel subfamily M member 2 (TRPM2) functioned as an upstream oxidative stress sensor to inhibit autophagy. Moreover, TRPM2‐mediated Ca2+ influx activated calpain to shear autophagy related 5 (Atg5) and Atg12–Atg5 conjugate formation was blocked to inhibit autophagy under oxidative stress. More importantly, Atg5 downregulation enhanced the binding of interferon regulatory factor 3 (IRF3) to the CXCL16 promoter region by activating Tank‐binding kinase 1 (TBK1), thus promoting CXCL16 secretion. These findings suggested that TRPM2‐restrained autophagy promotes CXCL16 secretion via the Atg5‐TBK1‐IRF3 signaling pathway under oxidative stress. Inhibition of TRPM2 may serve as a potential target for the treatment of vitiligo. © 2024 The Pathological Society of Great Britain and Ireland.

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Role of TRPM2 in brain tumours and potential as a drug target

Cited by 12 publications

References 148 publications

Pan-Cancer Analysis of the TRP Family, Especially TRPV4 and TRPC4, and Its Expression Correlated with Prognosis, Tumor Microenvironment, and Treatment Sensitivity

Pan-Cancer Analysis of the TRP Family, Especially TRPV4 and TRPC4, and Its Expression Correlated with Prognosis, Tumor Microenvironment, and Treatment Sensitivity

Transient receptor potential melastatin 2 channels in neurological disorders: Mechanisms and animal models

TRPM2‐dependent autophagy inhibition exacerbates oxidative stress‐induced CXCL16 secretion by keratinocytes in vitiligo

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