{"title":"Vemurafenib通过矛盾的ERK激活抑制5α-二氢睾酮分化的仓鼠皮脂细胞的mTOR通路","authors":"Toshikazu Koiwai, Takashi Sato","doi":"10.1111/exd.70150","DOIUrl":null,"url":null,"abstract":"<p>Vemurafenib, a low-molecular-weight BRAF inhibitor, effectively treats cutaneous melanoma with the BRAF<sup>V600E</sup> mutation, but it causes skin disorders such as dry skin with high frequency. As one of the factors causing skin dryness is a decrease in sebum production due to sebaceous gland dysfunction, we examined whether vemurafenib regulated the production and accumulation of sebum in hamster sebocytes. Vemurafenib dose- and time-dependently decreased the production and accumulation of sebum in DHT-differentiated hamster sebocytes. In addition, the DHT-augmented gene expressions of SCD-1, DGAT-1 and PLIN-1, which are involved in sebum production and accumulation in sebaceous glands, were suppressed by vemurafenib in hamster sebocytes. Unexpectedly, vemurafenib facilitated ERK phosphorylation in hamster sebocytes. In addition, DHT augmented the phosphorylation of ERK, under which vemurafenib synergistically enhanced the DHT-augmented phosphorylation. The enhanced ERK phosphorylation was no longer detectable by adding an ERK inhibitor, U0126. On the other hand, as mTOR plays an important role in the regulation of sebum production, the phosphorylation of Akt and 4EBP1, which are the upstream and downstream molecules in mTOR signalling, respectively, was increased in the DHT-treated hamster sebocytes. Vemurafenib inhibited the DHT-augmented 4EBP1 phosphorylation, which was no longer detectable in the presence of U0126. Furthermore, the suppression of the DHT-augmented sebum production and accumulation by vemurafenib was restored to their levels in DHT alone upon the U0126 treatment. Thus, these results provide novel evidence that vemurafenib suppresses sebum production and accumulation by the vemurafenib-activated ERK signalling that inhibits the Akt/mTOR pathway in DHT-differentiated hamster sebocytes.</p>","PeriodicalId":12243,"journal":{"name":"Experimental Dermatology","volume":"34 8","pages":""},"PeriodicalIF":3.1000,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/exd.70150","citationCount":"0","resultStr":"{\"title\":\"Suppression of Sebum Production by Vemurafenib Through Paradoxical ERK Activation Resulted in the Inhibition of the mTOR Pathway in 5α-Dihydrotestosterone-Differentiated Hamster Sebocytes In Vitro\",\"authors\":\"Toshikazu Koiwai, Takashi Sato\",\"doi\":\"10.1111/exd.70150\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Vemurafenib, a low-molecular-weight BRAF inhibitor, effectively treats cutaneous melanoma with the BRAF<sup>V600E</sup> mutation, but it causes skin disorders such as dry skin with high frequency. As one of the factors causing skin dryness is a decrease in sebum production due to sebaceous gland dysfunction, we examined whether vemurafenib regulated the production and accumulation of sebum in hamster sebocytes. Vemurafenib dose- and time-dependently decreased the production and accumulation of sebum in DHT-differentiated hamster sebocytes. In addition, the DHT-augmented gene expressions of SCD-1, DGAT-1 and PLIN-1, which are involved in sebum production and accumulation in sebaceous glands, were suppressed by vemurafenib in hamster sebocytes. Unexpectedly, vemurafenib facilitated ERK phosphorylation in hamster sebocytes. In addition, DHT augmented the phosphorylation of ERK, under which vemurafenib synergistically enhanced the DHT-augmented phosphorylation. The enhanced ERK phosphorylation was no longer detectable by adding an ERK inhibitor, U0126. On the other hand, as mTOR plays an important role in the regulation of sebum production, the phosphorylation of Akt and 4EBP1, which are the upstream and downstream molecules in mTOR signalling, respectively, was increased in the DHT-treated hamster sebocytes. Vemurafenib inhibited the DHT-augmented 4EBP1 phosphorylation, which was no longer detectable in the presence of U0126. Furthermore, the suppression of the DHT-augmented sebum production and accumulation by vemurafenib was restored to their levels in DHT alone upon the U0126 treatment. Thus, these results provide novel evidence that vemurafenib suppresses sebum production and accumulation by the vemurafenib-activated ERK signalling that inhibits the Akt/mTOR pathway in DHT-differentiated hamster sebocytes.</p>\",\"PeriodicalId\":12243,\"journal\":{\"name\":\"Experimental Dermatology\",\"volume\":\"34 8\",\"pages\":\"\"},\"PeriodicalIF\":3.1000,\"publicationDate\":\"2025-08-16\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1111/exd.70150\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Experimental Dermatology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1111/exd.70150\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"DERMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Experimental Dermatology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/exd.70150","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"DERMATOLOGY","Score":null,"Total":0}
Suppression of Sebum Production by Vemurafenib Through Paradoxical ERK Activation Resulted in the Inhibition of the mTOR Pathway in 5α-Dihydrotestosterone-Differentiated Hamster Sebocytes In Vitro
Vemurafenib, a low-molecular-weight BRAF inhibitor, effectively treats cutaneous melanoma with the BRAFV600E mutation, but it causes skin disorders such as dry skin with high frequency. As one of the factors causing skin dryness is a decrease in sebum production due to sebaceous gland dysfunction, we examined whether vemurafenib regulated the production and accumulation of sebum in hamster sebocytes. Vemurafenib dose- and time-dependently decreased the production and accumulation of sebum in DHT-differentiated hamster sebocytes. In addition, the DHT-augmented gene expressions of SCD-1, DGAT-1 and PLIN-1, which are involved in sebum production and accumulation in sebaceous glands, were suppressed by vemurafenib in hamster sebocytes. Unexpectedly, vemurafenib facilitated ERK phosphorylation in hamster sebocytes. In addition, DHT augmented the phosphorylation of ERK, under which vemurafenib synergistically enhanced the DHT-augmented phosphorylation. The enhanced ERK phosphorylation was no longer detectable by adding an ERK inhibitor, U0126. On the other hand, as mTOR plays an important role in the regulation of sebum production, the phosphorylation of Akt and 4EBP1, which are the upstream and downstream molecules in mTOR signalling, respectively, was increased in the DHT-treated hamster sebocytes. Vemurafenib inhibited the DHT-augmented 4EBP1 phosphorylation, which was no longer detectable in the presence of U0126. Furthermore, the suppression of the DHT-augmented sebum production and accumulation by vemurafenib was restored to their levels in DHT alone upon the U0126 treatment. Thus, these results provide novel evidence that vemurafenib suppresses sebum production and accumulation by the vemurafenib-activated ERK signalling that inhibits the Akt/mTOR pathway in DHT-differentiated hamster sebocytes.
期刊介绍:
Experimental Dermatology provides a vehicle for the rapid publication of innovative and definitive reports, letters to the editor and review articles covering all aspects of experimental dermatology. Preference is given to papers of immediate importance to other investigators, either by virtue of their new methodology, experimental data or new ideas. The essential criteria for publication are clarity, experimental soundness and novelty. Letters to the editor related to published reports may also be accepted, provided that they are short and scientifically relevant to the reports mentioned, in order to provide a continuing forum for discussion. Review articles represent a state-of-the-art overview and are invited by the editors.