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Sestrin2 Contributes to BRAF Inhibitor Resistance Via Reducing Redox Vulnerability of Melanoma Cells

  • Author Footnotes
    1 These authors contributed equally to this work
    Sen Guo
    Footnotes
    1 These authors contributed equally to this work
    Affiliations
    Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi 710032, China
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  • Author Footnotes
    1 These authors contributed equally to this work
    Qiao Yue
    Footnotes
    1 These authors contributed equally to this work
    Affiliations
    Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi 710032, China
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  • Author Footnotes
    1 These authors contributed equally to this work
    Shiyu Wang
    Footnotes
    1 These authors contributed equally to this work
    Affiliations
    Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi 710032, China
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  • Huina Wang
    Affiliations
    Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi 710032, China
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  • Zhubiao Ye
    Affiliations
    Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi 710032, China
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  • Weigang Zhang
    Affiliations
    Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi 710032, China
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  • Qiong Shi
    Affiliations
    Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi 710032, China
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  • Tianwen Gao
    Affiliations
    Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi 710032, China
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  • Chunying Li
    Affiliations
    Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi 710032, China
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  • Guannan Zhu
    Correspondence
    Correspondence to: Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi 710032, China. Tel./fax: + 86 29 8477 5406 8303
    Affiliations
    Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi 710032, China
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  • Author Footnotes
    1 These authors contributed equally to this work
Published:December 24, 2022DOI:https://doi.org/10.1016/j.jdermsci.2022.12.007

      HighLights

      • BRAFi resistant melanoma cells experienced significant increased level of Sestrin2, gaining protection from reactive oxidative stress (ROS)- induced cell death under BRAFi exposure.
      • The activity of mTOR signaling elevated following Sestrin2 ablation.
      • The combination of mTOR blocker and Sestrin2 knockdown generated enhanced growth suppression effects on BRAFi-resistant melanoma cells.

      Abstract

      Background

      Treatment resistance often occurs with BRAF inhibitor (BRAFi) therapy for melanoma, bringing in a great challenge to the treatment of melanoma patients harboring mutant BRAF gene. Recent studies revealed redox vulnerability constitutes a novel opportunity to overcome BRAFi resistance. Previously we found Sestrin2 provided protection to metastatic melanoma cells by detoxifying reactive oxygen species (ROS) induced by anoikis, but its defensive role against redox stimuli elicited by BRAFi was unclear.

      Objective

      In-depth explored the role of Sestrin2 in BRAFi-resistant melanoma.

      Methods

      Vemurafenib-resistant melanoma cells were established using 451Lu and UACC62 cell lines carrying BRAFV600E mutation. Mechanistic studies were subsequently performed by transfection of lentiviral vectors encoding an shRNA against SESN2 or embedded with the coding sequences of SESN2 cDNA.

      Results

      Elevated Sestrin2 expression was found in vemurafenib-resistance melanoma cells. Further mechanistic studies revealed that BRAFi-resistant melanoma cells employ Sestrin2 to adapt to higher oxidative stress under vemurafenib exposure. It was also demonstrated that mTOR signaling was significantly activated following Sestrin2 knockdown. Given the known promoting role of active mTOR signaling in melanoma proliferation and survival, the effects of mTOR blocker and Sestrin2 ablation on BRAFi-resistant melanoma cells were further tested, and the combination was found to result in enhanced inhibition of melanoma cell growth.

      Conclusions

      Our findings demonstrated the contribution of Sestrin2 to the development of BRAFi resistance and the fact that the combination of mTOR blocker assisted Sestrein2 ablation in eliminating BRAFi resistance of melanoma. Therefore, mTOR and Sestrin2 may be novel combinatorial therapeutic targets to overcome BRAFi resistance of melanoma.

      Keywords

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