Suppression of Nrf2-driven heme oxygenase-1 enhances the chemosensitivity of lung cancer A549 cells toward cisplatin.
Heme oxygenase-1 (HO-1) is highly expressed in various tumor tissues and plays an important role in tumor cell growth through anti-oxidative and anti-apoptotic effects. Herein, we demonstrate that A549 cells express high levels of HO-1, Nrf2, and NF-kappaB compared to other lung cancer cell lines, including H23, H157, and H460. Ectopic expression of HO-1 small interfering RNA (siRNA) increased both apoptosis and degradation of procaspase-3. Transfection studies with siRNA specific for Nrf2 and NF-kappaB revealed that HO-1 expression in A549 cells is mediated by transcriptional activation of Nrf2, but not NF-kappaB. A549 cells are less susceptible to cisplatin cytotoxicity than other lung cancer cell lines, concomitant with increases in HO-1 expression and MAPK phosphorylation in a time-dependent fashion. Furthermore, inhibition of HO-1 by siRNA and a specific HO-1 inhibitor ZnPP augments cisplatin cytotoxicity toward A549 cells. Pharmacologic suppression of HO-1 activity resulted in a marked increase in the ROS generation in cisplatin-treated cells. In addition, pharmacologic inhibitors of MAPK suppressed the induction of HO-1 and Nrf2 expression by cisplatin. These findings suggest that HO-1 may modulate the chemosensitivity of lung cancer A549 cells to cisplatin through the MAPK-Nrf2 pathway.
Kim
Hak-Ryul
HR
Department of Internal Medicine, Wonkwang University, School of Medicine, 344-2 Shinyong-dong Iksan, Jeonbuk 570-749, Republic of Korea.
Kim
Sejin
S
Microbiology, Wonkwang University, School of Medicine, Iksan, Jeonbuk, Republic of Korea.
Kim
Eun-Jung
EJ
Department of Internal Medicine, Wonkwang University, School of Medicine, 344-2 Shinyong-dong Iksan, Jeonbuk 570-749, Republic of Korea.
Park
Jung-Hyun
JH
Department of Internal Medicine, Wonkwang University, School of Medicine, 344-2 Shinyong-dong Iksan, Jeonbuk 570-749, Republic of Korea.
Yang
Sei-Hoon
SH
Department of Internal Medicine, Wonkwang University, School of Medicine, 344-2 Shinyong-dong Iksan, Jeonbuk 570-749, Republic of Korea.
Jeong
Eun-Taik
ET
Department of Internal Medicine, Wonkwang University, School of Medicine, 344-2 Shinyong-dong Iksan, Jeonbuk 570-749, Republic of Korea.
Park
Channy
C
Microbiology, Wonkwang University, School of Medicine, Iksan, Jeonbuk, Republic of Korea.
Youn
Myung-Ja
MJ
Microbiology, Wonkwang University, School of Medicine, Iksan, Jeonbuk, Republic of Korea.
So
Hong-Seob
HS
Microbiology, Wonkwang University, School of Medicine, Iksan, Jeonbuk, Republic of Korea.
Park
Raekil
R
Microbiology, Wonkwang University, School of Medicine, Iksan, Jeonbuk, Republic of Korea. Electronic address: rkpark@wonkwang.ac.kr.
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D051547:Heme Oxygenase-1 / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000502:physiology; D016328:NF-kappa B / Q000032:analysis; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D015533:Transcriptional Activation
D000970:Antineoplastic Agents; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495635:NFE2L2 protein, human; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D051547:Heme Oxygenase-1; D020928:Mitogen-Activated Protein Kinases; D002945:Cisplatin