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CAMKK2 Defines Ferroptosis Sensitivity of Melanoma Cells by Regulating AMPK‒NRF2 Pathway

  • Author Footnotes
    4 These authors contributed equally to this work.
    Sijia Wang
    Footnotes
    4 These authors contributed equally to this work.
    Affiliations
    Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, China

    Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
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  • Author Footnotes
    4 These authors contributed equally to this work.
    Xiuli Yi
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    4 These authors contributed equally to this work.
    Affiliations
    Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
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  • Author Footnotes
    4 These authors contributed equally to this work.
    Zhenjie Wu
    Footnotes
    4 These authors contributed equally to this work.
    Affiliations
    Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China

    Department of Bone and Soft Tissue Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
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  • Sen Guo
    Affiliations
    Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
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  • Wei Dai
    Affiliations
    Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, China

    Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
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  • Huina Wang
    Affiliations
    Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
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  • Qiong Shi
    Affiliations
    Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
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  • Author Footnotes
    5 These authors contributed equally to this work.
    Kang Zeng
    Footnotes
    5 These authors contributed equally to this work.
    Affiliations
    Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
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  • Author Footnotes
    5 These authors contributed equally to this work.
    Weinan Guo
    Footnotes
    5 These authors contributed equally to this work.
    Affiliations
    Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
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  • Author Footnotes
    5 These authors contributed equally to this work.
    Chunying Li
    Correspondence
    Correspondence: Chunying Li, Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
    Footnotes
    5 These authors contributed equally to this work.
    Affiliations
    Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
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  • Author Footnotes
    4 These authors contributed equally to this work.
    5 These authors contributed equally to this work.
      Melanoma is the most lethal skin cancer caused by the malignant transformation of epidermal melanocytes. Recent progress in targeted therapy and immunotherapy has significantly improved the treatment outcome, but the survival of patients with advanced melanoma remains suboptimal. Ferroptosis, a cell death modality triggered by iron-dependent lipid peroxidation, reportedly participates in cancer pathogenesis and can mediate the effect of anti–PD-1 immunotherapy in melanoma. However, the detailed regulatory mechanism of ferroptosis remains far from being understood. In this study, we report that CAMKK2 defines the ferroptosis sensitivity of melanoma cells by regulating the AMPK‒NRF2 pathway. We first found that CAMKK2 was prominently activated in ferroptosis. Then we proved that CAMKK2 negatively regulated ferroptosis through the activation of NRF2 and the suppression of lipid peroxidation. Subsequent mechanistic studies revealed that AMPK connected CAMKK2 upregulation to NRF2-dependent antioxidative machinery in ferroptosis. In addition, the suppression of CAMKK2 increased the efficacy of ferroptosis inducer and anti–PD-1 immunotherapy in the preclinical xenograft tumor model by inhibiting the AMPK‒NRF2 pathway and promoting ferroptosis. Taken together, CAMKK2 plays a protective role in ferroptosis by activating the AMPK‒NRF2 pathway. Targeting CAMKK2 could be a potential approach to increase the efficacy of ferroptosis inducers and immunotherapy for melanoma treatment.

      Abbreviations:

      Ca2+ (calcium ion), GSH (glutathione), MDA (malondialdehyde)
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