2. Academic Validation
  3. Cholesterol neutralized vemurafenib treatment by promoting melanoma stem-like cells via its metabolite 27-hydroxycholesterol

Cholesterol neutralized vemurafenib treatment by promoting melanoma stem-like cells via its metabolite 27-hydroxycholesterol

  • Cell Mol Life Sci. 2024 May 22;81(1):226. doi: 10.1007/s00018-024-05267-3.
Xiaohong Wang # 1 2,  Feiliang Zhong # 3,  Tingting Chen # 4,  Hongbo Wang 1 2,  Weifang Wang 1 2,  Hongkai Jin 1,  Chouyang Li 2,  Xuan Guo 1 2,  Ying Liu 1 2,  Yu Zhang 5 6,  Bo Li 7 8
Affiliations

Affiliations

  • 1 Liaoning Technology and Engineering Center for Tumor Immunology and Molecular Theranotics, Collaborative Innovation Center for Age-Related Disease, Life Science Institute of Jinzhou Medical University, Jinzhou, 121001, Liaoning, China.
  • 2 College of Basic Medical Science, Jinzhou Medical University, Jinzhou, 121001, Liaoning, China.
  • 3 Key Laboratory of Industrial Fermentation Microbiology of the Ministry of Education, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, People's Republic of China.
  • 4 School of Basic Medicine, Guangdong Medical University, Dongguan, 523808, Guangdong, China.
  • 5 Liaoning Technology and Engineering Center for Tumor Immunology and Molecular Theranotics, Collaborative Innovation Center for Age-Related Disease, Life Science Institute of Jinzhou Medical University, Jinzhou, 121001, Liaoning, China. [email protected].
  • 6 College of Basic Medical Science, Jinzhou Medical University, Jinzhou, 121001, Liaoning, China. [email protected].
  • 7 Liaoning Technology and Engineering Center for Tumor Immunology and Molecular Theranotics, Collaborative Innovation Center for Age-Related Disease, Life Science Institute of Jinzhou Medical University, Jinzhou, 121001, Liaoning, China. [email protected].
  • 8 College of Basic Medical Science, Jinzhou Medical University, Jinzhou, 121001, Liaoning, China. [email protected].
  • # Contributed equally.
PMID: 38775844 DOI: 10.1007/s00018-024-05267-3
Abstract

Vemurafenib has been used as first-line therapy for unresectable or metastatic melanoma with BRAFV600E mutation. However, overall survival is still limited due to treatment resistance after about one year. Therefore, identifying new therapeutic targets for melanoma is crucial for improving clinical outcomes. In the present study, we found that lowering intracellular Cholesterol by knocking down DHCR24, the limiting synthetase, impaired tumor cell proliferation and migration and abrogated the ability to xenotransplant tumors. More importantly, administration of DHCR24 or Cholesterol mediated resistance to vemurafenib and promoted the growth of melanoma spheroids. Mechanistically, we identified that 27-hydroxycholesterol (27HC), a primary metabolite of Cholesterol synthesized by the enzyme Cytochrome P450 27A1 (CYP27A1), reproduces the phenotypes induced by DHCR24 or Cholesterol administration and activates Rap1-PI3K/Akt signaling. Accordingly, CYP27A1 is highly expressed in melanoma patients and upregulated by DHCR24 induction. Dafadine-A, a CYP27A1 inhibitor, attenuates cholesterol-induced growth of melanoma spheroids and abrogates the resistance property of vemurafenib-resistant melanoma cells. Finally, we confirmed that the effects of Cholesterol on melanoma resistance require its metabolite 27HC through CYP27A1 catalysis, and that 27HC further upregulates Rap1A/Rap1B expression and increases Akt phosphorylation. Thus, our results suggest that targeting 27HC may be a useful strategy to overcome treatment resistance in metastatic melanoma.

Keywords

27-Hydroxycholesterol; Cholesterol metabolism; DHCR24; Melanoma.

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