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SorLA and CLC:CLF-1-dependent Downregulation of CNTFRα as Demonstrated by Western Blotting, Inhibition of Lysosomal Enzymes, and Immunocytochemistry
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SorLA and CLC:CLF-1-dependent Downregulation of CNTFRα as Demonstrated by Western Blotting, Inhibition of Lysosomal Enzymes, and Immunocytochemistry

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Effects of KEAP1 Silencing on NRF2 and NOTCH Pathways in SCLC Cell Lines

Federico Pio Fabrizio1,2,3, Angelo Sparaneo1, Giusy Gorgoglione1

  • 1Laboratory of Oncology, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy.

Cancers
|May 25, 2024
PubMed

Insights

Dysfunctional KEAP1/NRF2 signaling in small cell lung cancer (SCLC) promotes tumor growth and chemoresistance. Epigenetic silencing of KEAP1 disrupts NRF2 and NOTCH pathways, impacting cancer cell survival and drug response.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • The KEAP1/NRF2 pathway regulates genes involved in tumor cell drug resistance.
  • KEAP1/NRF2 system dysfunction correlates with patient outcomes and therapy response.
  • In lung tumors, NRF2/KEAP1 crosstalk with pathways like NOTCH impacts survival and drug resistance.

Purpose of the Study:

  • To investigate the genetic and epigenetic basis of NRF2/NOTCH crosstalk in SCLC.
  • To elucidate the role of KEAP1 dysfunction in SCLC tumorigenesis.
  • To assess the impact of KEAP1 modulation on SCLC response to chemotherapy and NOTCH inhibitors.

Main Methods:

  • Investigated genetic and epigenetic KEAP1 dysfunctions in SCLC cell lines.
  • Assessed the impact of KEAP1 modulation on response to etoposide, cisplatin, and DAPT.
  • Utilized siRNA to silence KEAP1 and analyzed downstream effects on NRF2 and NOTCH pathway components.

Main Results:

  • KEAP1/NRF2 axis is epigenetically controlled in SCLC cell lines.
  • KEAP1 silencing via siRNA upregulated NRF2, increasing chemoresistance to cisplatin and etoposide.
  • KEAP1 modulation affected transcription of NOTCH1, HES1, and DLL3.

Conclusions:

  • KEAP1 dysfunction epigenetically impacts NRF2 and NOTCH pathways in SCLC.
  • KEAP1/NRF2 and NOTCH pathway cooperation contributes to SCLC tumorigenesis.
  • These findings offer insights into SCLC treatment strategies targeting KEAP1/NRF2 and NOTCH signaling.
Keywords:
DLL-3HES1KEAP1NOTCHNRF2SCLC

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