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Updated: May 30, 2025

Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
04:01

Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics

Published on: March 15, 2024

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SPHK1 enhances olaparib resistance in ovarian cancer through the NFκB/NRF2/ferroptosis pathway

Kai Teng1, Hanlin Ma2,3, Panpan Gai4

  • 1Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China.

Cell Death Discovery
|January 28, 2025
PubMed

Insights

Sphingosine kinase 1 (SPHK1) promotes resistance to olaparib in ovarian cancer by inhibiting ferroptosis via the NF-κB/NRF2 pathway. Inhibiting SPHK1 enhances olaparib sensitivity and triggers ferroptosis, offering a potential therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Olaparib resistance is a significant challenge in ovarian cancer treatment.
  • The precise mechanisms underlying olaparib resistance, particularly the role of SPHK1, remain unclear.

Purpose of the Study:

  • To investigate the role of SPHK1 in olaparib resistance in ovarian cancer.
  • To elucidate the underlying molecular mechanisms, including the involvement of the NF-κB and ferroptosis pathways.

Main Methods:

  • High-throughput sequencing of olaparib-resistant SKOV3 cells (SK/Ola).
  • In vitro studies involving SPHK1 knockdown and treatment with SPHK1 inhibitor PF-543.
  • Analysis of NF-κB pathway activation, p-IκBα degradation, and ferroptosis induction.
  • In vivo experiments to validate findings.

Main Results:

  • SPHK1 was upregulated in olaparib-resistant cells and correlated with poor prognosis in ovarian cancer patients.
  • SPHK1 promoted olaparib resistance by activating the NF-κB pathway, leading to p-IκBα degradation.
  • SPHK1 inhibited ferroptosis, while its inhibition (via knockdown or PF-543) activated ferroptosis.
  • SPHK1 activated NF-κB p65, which transcriptionally regulated NRF2 to suppress ferroptosis.

Conclusions:

  • SPHK1 inhibition enhances olaparib sensitivity in ovarian cancer by triggering ferroptosis through the suppression of NF-κB-activated NRF2 transcription.
  • Combination therapy with SPHK1 inhibitors and olaparib shows promise for treating ovarian cancer.

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