Nuclear factor erythroid 2-related factor-2 activity controls 4-hydroxynonenal metabolism and activity in prostate cancer cells

Piergiorgio Pettazzoni, Eric Ciamporcero, Claudio Medana, Stefania Pizzimenti, Federica Dal Bello, Valerio Giacomo Minero, Cristina Toaldo, Rosalba Minelli, Koji Uchida, Mario Umberto Dianzani, Roberto Pili, Giuseppina Barrera

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23 Scopus citations

Abstract

4-Hydroxynonenal (HNE) is an end product of lipoperoxidation with antiproliferative and proapoptotic properties in various tumors. Here we report a greater sensitivity to HNE in PC3 and LNCaP cells compared to DU145 cells. In contrast to PC3 and LNCaP cells, HNE-treated DU145 cells showed a smaller reduction in growth and did not undergo apoptosis. In DU145 cells, HNE did not induce ROS production and DNA damage and generated a lower amount of HNE-protein adducts. DU145 cells had a greater GSH and GST A4 content and GSH/GST-mediated HNE detoxification. Nuclear factor erythroid 2-related factor-2 (Nrf2) is a regulator of the antioxidant response. Nrf2 protein content and nuclear accumulation were higher in DU145 cells compared to PC3 and LNCaP cells, whereas the expression of KEAP1, the main negative regulator of Nrf2 activity, was lower. Inhibition of Nrf2 expression with specific siRNA resulted in a reduction in GST A4 expression and GS-HNE formation, indicating that Nrf2 controls HNE metabolism. In addition, Nrf2 knockdown sensitized DU145 cells to HNE-mediated antiproliferative and proapoptotic activity. In conclusion, we demonstrated that increased Nrf2 activity resulted in a reduction in HNE sensitivity in prostate cancer cells, suggesting a potential mechanism of resistance to pro-oxidant therapy.

Original languageEnglish (US)
Pages (from-to)1610-1618
Number of pages9
JournalFree Radical Biology and Medicine
Volume51
Issue number8
DOIs
StatePublished - Oct 15 2011

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Keywords

  • 4-Hydroxynonenal
  • Aldehyde metabolism
  • Apoptosis
  • DNA damage
  • Free radicals
  • GS-HNE adduct
  • GST A4
  • Glutathione
  • KEAP1
  • Nrf2
  • Oxidative stress
  • Prostate cancer

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this

Pettazzoni, P., Ciamporcero, E., Medana, C., Pizzimenti, S., Dal Bello, F., Minero, V. G., Toaldo, C., Minelli, R., Uchida, K., Dianzani, M. U., Pili, R., & Barrera, G. (2011). Nuclear factor erythroid 2-related factor-2 activity controls 4-hydroxynonenal metabolism and activity in prostate cancer cells. Free Radical Biology and Medicine, 51(8), 1610-1618. https://doi.org/10.1016/j.freeradbiomed.2011.07.009