Oxyresveratrol Inhibits TNF-α-Stimulated Cell Proliferation in Human Immortalized Keratinocytes (HaCaT) by Suppressing AKT Activation
Psoriasis is a complex inflammatory disease characterized by hyperproliferative keratinocyte caused by active PI3K/AKT signaling. TNF-α concentrated in the psoriatic lesions stimulates AKT activation. We previously discovered that oxyresveratrol inhibited inflammation via suppressing AKT phosphoryla...
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MDPI AG
2021-12-01
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| Series: | Pharmaceutics |
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| author | Nitwara Wikan Phateep Hankittichai Phatarawat Thaklaewphan Saranyapin Potikanond Wutigri Nimlamool |
| author_facet | Nitwara Wikan Phateep Hankittichai Phatarawat Thaklaewphan Saranyapin Potikanond Wutigri Nimlamool |
| author_sort | Nitwara Wikan |
| collection | DOAJ |
| description | Psoriasis is a complex inflammatory disease characterized by hyperproliferative keratinocyte caused by active PI3K/AKT signaling. TNF-α concentrated in the psoriatic lesions stimulates AKT activation. We previously discovered that oxyresveratrol inhibited inflammation via suppressing AKT phosphorylation, therefore oxyresveratrol may possess a conserved property to block AKT activation and proliferation in keratinocyte in response to TNF-α. Our current study proved that oxyresveratrol exhibited potent anti-proliferative effects against TNF-α. These effects are explained by the findings that oxyresveratrol could potentially inhibit TNF-α-stimulated AKT and GSK3-<sub>β</sub> activation in a dose-dependent manner, and its inhibitory pattern was comparable to that of a specific PI3K inhibitor. Results from immunofluorescence supported that oxyresveratrol effectively inhibited AKT and GSK3-<sub>β</sub> activation in individual cells upon TNF-α stimulation. Furthermore, functional assay confirmed that oxyresveratrol repressed the expansion of the HaCaT colony over 3 days, and this was caused by the ability of oxyresveratrol to induce cell cycle arrest at S and G2/M phases and the reduction in the expression of a proliferative marker (Ki-67) and a survival marker (MCL-1). Given the importance of TNF-α and the PI3K/AKT pathway in the psoriatic phenotype, we anticipate that oxyresveratrol, which targets the TNF-α-stimulated PI3K/AKT pathway, would represent a promising psoriasis therapy in the near future. |
| first_indexed | 2024-03-10T00:43:59Z |
| format | Article |
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| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T00:43:59Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-3aa1581da55640cab92cc0be4417bcaf2023-11-23T15:03:18ZengMDPI AGPharmaceutics1999-49232021-12-011416310.3390/pharmaceutics14010063Oxyresveratrol Inhibits TNF-α-Stimulated Cell Proliferation in Human Immortalized Keratinocytes (HaCaT) by Suppressing AKT ActivationNitwara Wikan0Phateep Hankittichai1Phatarawat Thaklaewphan2Saranyapin Potikanond3Wutigri Nimlamool4Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, ThailandDepartment of Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, ThailandDepartment of Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, ThailandDepartment of Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, ThailandDepartment of Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, ThailandPsoriasis is a complex inflammatory disease characterized by hyperproliferative keratinocyte caused by active PI3K/AKT signaling. TNF-α concentrated in the psoriatic lesions stimulates AKT activation. We previously discovered that oxyresveratrol inhibited inflammation via suppressing AKT phosphorylation, therefore oxyresveratrol may possess a conserved property to block AKT activation and proliferation in keratinocyte in response to TNF-α. Our current study proved that oxyresveratrol exhibited potent anti-proliferative effects against TNF-α. These effects are explained by the findings that oxyresveratrol could potentially inhibit TNF-α-stimulated AKT and GSK3-<sub>β</sub> activation in a dose-dependent manner, and its inhibitory pattern was comparable to that of a specific PI3K inhibitor. Results from immunofluorescence supported that oxyresveratrol effectively inhibited AKT and GSK3-<sub>β</sub> activation in individual cells upon TNF-α stimulation. Furthermore, functional assay confirmed that oxyresveratrol repressed the expansion of the HaCaT colony over 3 days, and this was caused by the ability of oxyresveratrol to induce cell cycle arrest at S and G2/M phases and the reduction in the expression of a proliferative marker (Ki-67) and a survival marker (MCL-1). Given the importance of TNF-α and the PI3K/AKT pathway in the psoriatic phenotype, we anticipate that oxyresveratrol, which targets the TNF-α-stimulated PI3K/AKT pathway, would represent a promising psoriasis therapy in the near future.https://www.mdpi.com/1999-4923/14/1/63psoriasisPI3KAKTkeratinocyteHaCaT cellsproliferation |
| spellingShingle | Nitwara Wikan Phateep Hankittichai Phatarawat Thaklaewphan Saranyapin Potikanond Wutigri Nimlamool Oxyresveratrol Inhibits TNF-α-Stimulated Cell Proliferation in Human Immortalized Keratinocytes (HaCaT) by Suppressing AKT Activation Pharmaceutics psoriasis PI3K AKT keratinocyte HaCaT cells proliferation |
| title | Oxyresveratrol Inhibits TNF-α-Stimulated Cell Proliferation in Human Immortalized Keratinocytes (HaCaT) by Suppressing AKT Activation |
| title_full | Oxyresveratrol Inhibits TNF-α-Stimulated Cell Proliferation in Human Immortalized Keratinocytes (HaCaT) by Suppressing AKT Activation |
| title_fullStr | Oxyresveratrol Inhibits TNF-α-Stimulated Cell Proliferation in Human Immortalized Keratinocytes (HaCaT) by Suppressing AKT Activation |
| title_full_unstemmed | Oxyresveratrol Inhibits TNF-α-Stimulated Cell Proliferation in Human Immortalized Keratinocytes (HaCaT) by Suppressing AKT Activation |
| title_short | Oxyresveratrol Inhibits TNF-α-Stimulated Cell Proliferation in Human Immortalized Keratinocytes (HaCaT) by Suppressing AKT Activation |
| title_sort | oxyresveratrol inhibits tnf α stimulated cell proliferation in human immortalized keratinocytes hacat by suppressing akt activation |
| topic | psoriasis PI3K AKT keratinocyte HaCaT cells proliferation |
| url | https://www.mdpi.com/1999-4923/14/1/63 |
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