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P62/SQSTM1/Keap1/NRF2 Axis Reduces Cancer Cells Death-Sensitivity in Response to Zn(II)-Curcumin Complex

Alessia Garufi1,2, Eugenia Giorno3, Maria Saveria Gilardini Montani4

  • 1Unit of Cellular Networks, Department of Research and Advanced Technologies, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy.

Biomolecules
|March 6, 2021
PubMed

Insights

Zinc-curcumin (Zn(II)-curc) activates nuclear factor erythroid 2 p45-related factor 2 (NRF2) by inhibiting Keap1. This activation enhances cancer cell death, suggesting a new therapeutic strategy for improving cancer treatment response.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Hyperactivation of nuclear factor erythroid 2 p45-related factor 2 (NRF2) is linked to cancer therapy resistance and poor prognosis.
  • Curcumin's role in NRF2 activation is context-dependent, showing both protective and tumor-promoting effects.

Purpose of the Study:

  • To investigate the effect of zinc-curcumin (Zn(II)-curc) on NRF2 activation.
  • To elucidate the molecular mechanisms underlying Zn(II)-curc-induced NRF2 activation.
  • To explore the therapeutic potential of targeting the NRF2 pathway with Zn(II)-curc.

Main Methods:

  • Biochemical assays to measure protein levels of NRF2, heme oxygenase-1 (HO-1), p62/SQSTM1, and Keap1.
  • RNA interference (siRNA) to silence NRF2 and p62/SQSTM1.
  • Assessment of cancer cell sensitivity to Zn(II)-curc-induced cell death.

Main Results:

  • Zn(II)-curc treatment increased NRF2 protein levels and its downstream targets HO-1 and p62/SQSTM1.
  • Zn(II)-curc treatment reduced the levels of Keap1, the NRF2 inhibitor.
  • Silencing NRF2 or p62/SQSTM1 enhanced cancer cell sensitivity to Zn(II)-curc, indicating a crosstalk between these molecules.

Conclusions:

  • Zn(II)-curc activates NRF2 by inhibiting Keap1.
  • The crosstalk between p62/SQSTM1 and NRF2 plays a crucial role in mediating Zn(II)-curc's anticancer effects.
  • Targeting the NRF2-p62/SQSTM1 pathway with Zn(II)-curc represents a promising therapeutic strategy to enhance cancer patient response to treatments.
Keywords:
Keap1NRF2cancer cellsdrug sensitivityp53p62/SQSTM1zinc compounds

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