title: Nrf2-dependent induction of human ABC transporter ABCG2 and heme oxygenase-1 in HepG2 cells by photoactivation of porphyrins: biochemical implications for cancer cell response to photodynamic therapy.
abstract: Photodynamic therapy is a recently developed anticancer treatment that utilizes the generation of singlet oxygen and other reactive oxygen species in cancer tissue. Nrf2, an NF-E2-related transcription factor, plays a pivotal role in transcriptional upregulation of many target genes, including those for metabolizing enzymes and transporters essential for cellular defense in response to oxidative stress. In the present study, we examined the potential involvement of Nrf2 in the induction of human ABC transporter ABCG2 and heme oxygenase-1 (HO-1). When HepG2 cells were incubated with non-toxic concentrations of delta-aminolevulinic acid, protoporphyrin IX, or pheophorbide a and then exposed to visible light for 90 min, the mRNA level of HO-1 began increasing markedly, reaching the maximal level in 4 h. Following the transient induction of HO-1, the mRNA level of ABCG2 gradually increased in a time-dependent manner, whereas the ABCB6 mRNA level was little affected. Nrf2-specific siRNA treatments suppressed the induction of both ABCG2 and HO-1 after the photoactivation of porphyrins, suggesting that Nrf2 is a common regulator for transcriptional activation of the ABCG2 and HO-1 genes. On the other hand, the mRNA level of HO-1 was remarkably enhanced by Zn(2+)-protoporphyrin IX or hemin even in the absence of light. This induction may be attributed to inactivation of Bach1, a repressor for the HO-1 gene, by those compounds. Since patients have demonstrated individual defferences in their response to photodynamic therapy, transcriptional activation of the ABCG2 and HO-1 genes in cancer cells may affect patients' responses to photodynamic therapy.
authors.affiliation: Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta, Midori-ku, Yokohama 226-8501, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Hagiya
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Adachi
authors.forename: Shun-ichiro
authors.initials: S
authors.lastname: Ogura
authors.forename: Ran
authors.initials: R
authors.lastname: An
authors.forename: Ai
authors.initials: A
authors.lastname: Tamura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakagawa
authors.forename: Ichiro
authors.initials: I
authors.lastname: Okura
authors.forename: Tohru
authors.initials: T
authors.lastname: Mochizuki
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Ishikawa
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics; D000622:Aminolevulinic Acid / Q000494:pharmacology; D052160:Benzothiazoles; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002734:Chlorophyll / Q000031:analogs & derivatives / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D003959:Diamines; D004591:Electrophoresis, Polyacrylamide Gel; D005456:Fluorescent Dyes; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000502:physiology*; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D009369:Neoplasms / Q000473:pathology / Q000628:therapy*; D009930:Organic Chemicals; D018384:Oxidative Stress; D010777:Photochemistry; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000494:pharmacology; D011166:Porphyrins / Q000737:chemistry* / Q000528:radiation effects*; D011524:Protoporphyrins / Q000494:pharmacology; D011804:Quinolines; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D014162:Transfection
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D052160:Benzothiazoles; D003959:Diamines; D005456:Fluorescent Dyes; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D009363:Neoplasm Proteins; D009930:Organic Chemicals; D017319:Photosensitizing Agents; D011166:Porphyrins; D011524:Protoporphyrins; D011804:Quinolines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D002734:Chlorophyll; C098022:SYBR Green I; D000622:Aminolevulinic Acid; C028025:protoporphyrin IX; D051547:Heme Oxygenase-1; C032623:pheophorbide a