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

Xiaohong Wang1,2, Feiliang Zhong3, Tingting Chen4

  • 1Liaoning 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.

Cellular and Molecular Life Sciences : CMLS
|May 22, 2024
PubMed

Insights

Targeting cholesterol metabolism by inhibiting DHCR24 or its metabolite 27-hydroxycholesterol (27HC) can overcome vemurafenib resistance in melanoma. This approach may improve outcomes for patients with metastatic melanoma.

Area of Science:

  • Oncology
  • Biochemistry
  • Molecular Biology

Background:

  • Vemurafenib is a first-line therapy for BRAFV600E-mutated metastatic melanoma.
  • Treatment resistance limits vemurafenib's overall survival benefit, necessitating new therapeutic targets.

Purpose of the Study:

  • To investigate the role of cholesterol metabolism in vemurafenib resistance in melanoma.
  • To identify novel therapeutic strategies to overcome treatment resistance.

Main Methods:

  • Knockdown of DHCR24 (24-dehydrocholesterol reductase) to reduce intracellular cholesterol.
  • Administration of DHCR24, cholesterol, or 27-hydroxycholesterol (27HC).
  • Inhibition of CYP27A1 (cytochrome P450 27A1) using Dafadine-A.
  • Analysis of melanoma cell proliferation, migration, spheroid growth, and signaling pathways (Rap1-PI3K/AKT).

Main Results:

  • Lowering intracellular cholesterol via DHCR24 knockdown impaired melanoma cell proliferation, migration, and tumor xenotransplantation.
  • DHCR24 or cholesterol administration induced vemurafenib resistance and promoted melanoma spheroid growth.
  • 27HC, a cholesterol metabolite synthesized by CYP27A1, mimicked these effects and activated Rap1-PI3K/AKT signaling.
  • CYP27A1 was highly expressed in melanoma patients and upregulated by DHCR24.
  • Dafadine-A attenuated cholesterol-induced growth and abrogated vemurafenib resistance in resistant cells.
  • Cholesterol's effects on melanoma resistance depend on 27HC production via CYP27A1, leading to upregulated Rap1A/1B and increased AKT phosphorylation.

Conclusions:

  • Targeting 27HC, a key cholesterol metabolite, represents a promising strategy to overcome vemurafenib resistance in metastatic melanoma.
  • Inhibition of CYP27A1 may reverse acquired resistance to vemurafenib.
Keywords:
27-HydroxycholesterolCholesterol metabolismDHCR24Melanoma

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