title: Nuclear factor erythroid 2-related factor-2 activity controls 4-hydroxynonenal metabolism and activity in prostate cancer cells.
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.
authors.affiliation: Section of General Pathology, Department of Medicine and Experimental Oncology, University of Turin, 10125 Turin, Italy. piergiorgio.pettazzoni@unito.it
authors.forename: Piergiorgio
authors.initials: P
authors.lastname: Pettazzoni
authors.forename: Eric
authors.initials: E
authors.lastname: Ciamporcero
authors.forename: Claudio
authors.initials: C
authors.lastname: Medana
authors.forename: Stefania
authors.initials: S
authors.lastname: Pizzimenti
authors.forename: Federica
authors.initials: F
authors.lastname: Dal Bello
authors.forename: Valerio Giacomo
authors.initials: VG
authors.lastname: Minero
authors.forename: Cristina
authors.initials: C
authors.lastname: Toaldo
authors.forename: Rosalba
authors.initials: R
authors.lastname: Minelli
authors.forename: Koji
authors.initials: K
authors.lastname: Uchida
authors.forename: Mario Umberto
authors.initials: MU
authors.lastname: Dianzani
authors.forename: Roberto
authors.initials: R
authors.lastname: Pili
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Barrera
mesh_terms: D000447:Aldehydes / Q000378:metabolism* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects; D005786:Gene Expression Regulation / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015227:Lipid Peroxidation / Q000235:genetics; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000447:Aldehydes; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D005982:Glutathione Transferase; C041116:leukotriene-C4 synthase; C027576:4-hydroxy-2-nonenal