Novel approaches to vitiligo treatment via modulation of mTOR and NF-κB pathways in human skin melanocytes

Wan, Jerry; Lin, Fuquan; Zhang, Wei; Xu, Aie; DeGiorgis, Joseph A.; Lü, Hongguang; Wan, Yinsheng

doi:10.7150/ijbs.17318

Cited by 25 publications

(30 citation statements)

References 55 publications

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“…Furthermore, another study suggested that α-melanocyte-stimulating hormone stimulated melanogenesis through activating the mitogen-activated protein kinase kinase/ERK or PI3K/AKT pathways (20). Regulation of the PI3K/AKT/mTOR signaling pathway has been reported to be a novel approach for the clinical treatment of vitiligo (21). Moreover, the association between RIPK1 and the PI3K/AKT/mTOR pathway in melanocytes under ER stress remains largely unclear.…”

Section: Introductionmentioning

confidence: 99%

RIPK1 regulates the survival of human melanocytes upon endoplasmic reticulum stress

et al. 2020

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Vitiligo is a common congenital or acquired disfiguring skin disorder. At present, endoplasmic reticulum (ER) stress has been identified to serve a critical role in the pathogenesis of vitiligo. Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a protein serine/threonine kinase. The specific molecular mechanism of RIPK1 in human melanocytes upon ER stress remains to be determined. In the present study, RIPK1 was significantly downregulated in tunicamycin (TM)-induced ER stressed-human melanocytes. Subsequently, to explore the role of RIPK1 in ER stress-induced human melanocytes, human melanocytes were transfected with control or RIPK1 plasmids for 24 h and then treated with 3 µM TM for 48 h. Reverse transcription-quantitative PCR and western blot analysis indicated that the expression levels of protein kinase R-like endoplasmic reticulum kinase, eukaryotic translation initiation factor 2 subunit 1 and CCAAT-enhancer-binding protein homologous protein were significantly increased in the TM-treated group compared with the controls. In addition, the effect of high RIPK1 expression on ER stress-induced human melanocyte survival was studied. The present results indicated that TM inhibited cell viability and promoted apoptosis in human primary epidermal melanocytes. Western blot analysis demonstrated that the expression of Bax and caspase-3 was upregulated and the expression of Bcl-2 was downregulated in TM-treated human melanocytes. The effects of TM on human melanocytes were reversed by RIPK1 overexpression. Therefore, RIPK1 overexpression may have an effect on the PI3K/AKT/mTOR signaling pathway in human melanocytes under ER stress. The results of the current study demonstrated that RIPK1 could protect human melanocytes from cell damage induced by ER stress by regulating the PI3K/AKT/mTOR and ER stress signaling pathways, thereby serving a protective role in the occurrence and development of vitiligo.

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Section: Introductionmentioning

confidence: 99%

RIPK1 regulates the survival of human melanocytes upon endoplasmic reticulum stress

et al. 2020

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“…a previous study indicated that nrf2 negatively regulates melanogenesis by modulating the Pi3K/akt signaling pathway (42). The α-MSH-induced activation of the mTorc1 pathway, inhibited by rapamycin, helps to maintain dendrites of melanocytes under oxidative stress (26). Sustained Pi3K activity can protect melanocytes from apoptosis, thereby indicating that the Pi3K/aKT pathway plays a pivotal role in melanocyte survival (43).…”

Section: Discussionmentioning

confidence: 97%

“…in addition, indirect data indicated that α-MSH stimulated melanogenesis through the activation of the MeK/erK or Pi3K/aKT pathways (25). Modulation of the Pi3K/aKT and mTor pathway may be a novel approach to the clinical management of vitiligo (26). a previous study indicated that nrf2 negatively regulates melanogenesis by modulating the Pi3K/akt signaling pathway (42).…”

Section: Discussionmentioning

confidence: 99%

“…in addition, indirect data indicated that α-melanocyte-stimulating hormone (MSH) stimulates melanogenesis through the activation of MeK/extracellular signal-regulated kinase (erK) or Pi3K/aKT (25). Modulation of the Pi3K/aKT/mTor signaling pathway may be a novel approach to the clinical management of vitiligo (26). However, the association between mir-421 and the Pi3K/aKT/mTor pathway in melanocytes under er stress remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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microRNA‑421 participates in vitiligo development through regulating human melanocyte survival by targeting receptor‑interacting serine/threonine kinase 1

et al. 2019

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Vitiligo is a common localized or generalized skin pigmentation disorder. endoplasmic reticulum (er) stress may be implicated in the development of vitiligo. microrna-421 (mir-421) has been reported to be dysregulated in various human tumors. However, there is no report to date on the role of mir-421 in vitiligo development. The present study demonstrated that 3 µM tunicamycin (TM) increased the expression of the er stress-related proteins protein kinase rna-like endoplasmic reticulum kinase (PerK), α subunit of eukaryotic translation initiation factor 2 (eiF2α) and c/eBP homologous protein (cHoP) in human primary epidermal melanocytes. Moreover, TM suppressed melanocyte viability and induced apoptosis. reverse transcription-quantitative Pcr analysis demonstrated that TM promoted mir-421 expression in human melanocytes. next, TargetScan and dual luciferase reporter gene assay indicated that receptor-interacting serine/threonine kinase 1 (riPK1) was a direct target of mir-421. riPK1 expression was significantly downregulated in TM-induced human melanocytes. Subsequently, the effect of mir-421 downregulation on the damage of human melanocytes induced by er stress was investigated. Human melanocytes were transfected with inhibitor control, mir-421 inhibitor, mir-421 inhibitor + control-short hairpin (sh)rna, or mir-421 inhibitor + riPK1-shrna for 24 h and then treated with TM (3 µM) for 48 h. TM was found to upregulate PerK, eiF2α and cHoP protein expression in human melanocytes, which was reduced by an mir-421 inhibitor. in addition, the mir-421 inhibitor increased viability and reduced apoptosis in TM-treated melanocytes. Furthermore, all these effects of the mir-421 inhibitor on TM-induced human melanocytes were reversed by riPK1-shrna. Further analyses revealed that the mir-421 inhibitor activated the phosphoinositide 3 kinase/protein kinase B/mammalian target of rapamycin signaling pathway in TM-induced human melanocytes. These data collectively suggest that mir-421 may serve as a new treatment target in vitiligo development.

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“…Although the mechanism involved in this type of druginduced vitiligo isn't completely clear, we can suppose that one of the pathogenetic mechanisms is that everolimus can inhibit melanogenesis, by inhibiting the protective mTORC1 pathway against oxidative stress. 16 Our case can suggest a new possible type of drug melanocyte-specific toxicity.…”

Section: Discussionmentioning

confidence: 99%

Vitiligo: A new side effect of everolimus therapy for metastatic renal cell carcinoma

Cacciapuoti

Masarà

Mariano

et al. 2017

AMJ

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Patients with metastatic renal cell carcinoma (mRCC) have always had a poor prognosis. Recently new targeted drugs were developed. A 73-year-old female patient affected from mRCC was assessed at our Department. She underwent before a multitargeted tyrosine kinase inhibitor (TKI) therapy, but she developed progressive liver metastases so she was treated after with everolimus, an allosteric inhibitor of the mammalian target of rapamycin (mTOR), but started developing depigmented lesions over the neck. Vitiligo is a common cutaneous disorder and drug-induced vitiligo is reported. Our case can suggest a new type of drug-induced vitiligo, caused by a melanocyte-specific mechanism of toxicity.

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Novel approaches to vitiligo treatment via modulation of mTOR and NF-κB pathways in human skin melanocytes

Cited by 25 publications

References 55 publications

RIPK1 regulates the survival of human melanocytes upon endoplasmic reticulum stress

RIPK1 regulates the survival of human melanocytes upon endoplasmic reticulum stress

microRNA‑421 participates in vitiligo development through regulating human melanocyte survival by targeting receptor‑interacting serine/threonine kinase 1

Vitiligo: A new side effect of everolimus therapy for metastatic renal cell carcinoma

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