title: Cancer growth regulation by 4-hydroxynonenal.
abstract: While reactive oxygen species (ROS) gain their carcinogenic effects by DNA mutations, if generated in the vicinity of genome, lipid peroxidation products, notably 4-hydroxynonenal (HNE), have much more complex modes of activities. Namely, while ROS are short living and have short efficiency distance range (in nm or µm) HNE has strong binding affinity for proteins, thus forming relatively stable adducts. Hence, HNE can diffuse from the site or origin changing structure and function of respective proteins. Consequently HNE can influence proliferation, differentiation and apoptosis of cancer cells on one hand, while on the other it can affect genome functionality, too. Although HNE is considered to be important factor of carcinogenesis due to its ability to covalently bind to DNA, it might also be cytotoxic for cancer cells, as well as it can modulate their growth. In addition to direct cytotoxicity, HNE is also involved in activity mechanisms by which several cytostatic drugs and radiotherapy exhibit their anticancer effects. Complementary to that, the metabolic pathway for HNE detoxification through RLIP76, which is enhanced in cancer, may be a target for anti-cancer treatments. In addition, some cancer cells can undergo apoptosis or necrosis, if exposed to supraphysiological HNE levels in the cancer microenvironment, especially if challenged additionally by pro-oxidative cytostatics and/or inflammation. These findings could explain previously observed disappearance of HNE from invading cancer cells, which is associated with the increase of HNE in non-malignant cells close to invading cancer utilizing cardiolipin as the source of cancer-inhibiting HNE.
authors.affiliation: Rudjer Boskovic Institute, Bijenicka 54, Zagreb, Croatia.
authors.forename: Ana Cipak
authors.initials: AC
authors.lastname: Gasparovic
authors.affiliation: Rudjer Boskovic Institute, Bijenicka 54, Zagreb, Croatia.
authors.forename: Lidija
authors.initials: L
authors.lastname: Milkovic
authors.affiliation: Rudjer Boskovic Institute, Bijenicka 54, Zagreb, Croatia.
authors.forename: Suzana Borovic
authors.initials: SB
authors.lastname: Sunjic
authors.affiliation: Rudjer Boskovic Institute, Bijenicka 54, Zagreb, Croatia. Electronic address: zarkovic@irb.hr.
authors.forename: Neven
authors.initials: N
authors.lastname: Zarkovic
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000447:Aldehydes / Q000378:metabolism* / Q000494:pharmacology; D063646:Carcinogenesis / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002308:Cardiolipins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D020690:GTPase-Activating Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; D000447:Aldehydes; D002308:Cardiolipins; D020690:GTPase-Activating Proteins; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495635:NFE2L2 protein, human; C095637:RALBP1 protein, human; D016159:Tumor Suppressor Protein p53; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C; C027576:4-hydroxy-2-nonenal
keywords: 4-Hydroxynonenal (HNE); Cancer; Cancer therapy; Carcinogenesis; Growth regulation; Lipid peroxidation; Oxidative stress; Pathophysiology; Signaling