title: Heme oxygenase-1 determines the differential response of breast cancer and normal cells to piperlongumine.
abstract: Piperlongumine, a natural alkaloid isolated from the long pepper, selectively increases reactive oxygen species production and apoptotic cell death in cancer cells but not in normal cells. However, the molecular mechanism underlying piperlongumine-induced selective killing of cancer cells remains unclear. In the present study, we observed that human breast cancer MCF-7 cells are sensitive to piperlongumine-induced apoptosis relative to human MCF-10A breast epithelial cells. Interestingly, this opposing effect of piperlongumine appears to be mediated by heme oxygenase-1 (HO-1). Piperlongumine upregulated HO-1 expression through the activation of nuclear factor-erythroid-2-related factor-2 (Nrf2) signaling in both MCF-7 and MCF-10A cells. However, knockdown of HO-1 expression and pharmacological inhibition of its activity abolished the ability of piperlongumine to induce apoptosis in MCF-7 cells, whereas those promoted apoptosis in MCF-10A cells, indicating that HO-1 has anti-tumor functions in cancer cells but cytoprotective functions in normal cells. Moreover, it was found that piperlongumine-induced Nrf2 activation, HO-1 expression and cancer cell apoptosis are not dependent on the generation of reactive oxygen species. Instead, piperlongumine, which bears electrophilic α,β-unsaturated carbonyl groups, appears to inactivate Kelch-like ECH-associated protein-1 (Keap1) through thiol modification, thereby activating the Nrf2/HO-1 pathway and subsequently upregulating HO-1 expression, which accounts for piperlongumine-induced apoptosis in cancer cells. Taken together, these findings suggest that direct interaction of piperlongumine with Keap1 leads to the upregulation of Nrf2-mediated HO-1 expression, and HO-1 determines the differential response of breast normal cells and cancer cells to piperlongumine.
authors: KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, Seoul 139-709, Korea.
authors: Ha-Na
authors: HN
authors: Lee
authors: KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, Seoul 139-709, Korea.
authors: Hyeon-Ok
authors: HO
authors: Jin
authors: KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, Seoul 139-709, Korea.
authors: Jin-Ah
authors: JA
authors: Park
authors: KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, Seoul 139-709, Korea.
authors: Jin-Hee
authors: JH
authors: Kim
authors: KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, Seoul 139-709, Korea.
authors: Ji-Young
authors: JY
authors: Kim
authors: KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, Seoul 139-709, Korea.
authors: BoRa
authors: B
authors: Kim
authors: College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
authors: Wonki
authors: W
authors: Kim
authors: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul 139-709, Korea.
authors: Sung-Eun
authors: SE
authors: Hong
authors: Department of Radiation Oncology, College of Medicine, Yonsei University, Seoul 120-752, Korea.
authors: Yun-Han
authors: YH
authors: Lee
authors: Department of Laboratory Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul 139-709, Korea.
authors: Yoon Hwan
authors: YH
authors: Chang
authors: Department of Laboratory Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul 139-709, Korea.
authors: Seok-Il
authors: SI
authors: Hong
authors: Department of Laboratory Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul 139-709, Korea.
authors: Young Jun
authors: YJ
authors: Hong
authors: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul 139-709, Korea.
authors: In-Chul
authors: IC
authors: Park
authors: College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
authors: Young-Joon
authors: YJ
authors: Surh
authors: KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, Seoul 139-709, Korea.|Department of Laboratory Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul 139-709, Korea.
authors: Jin Kyung
authors: JK
authors: Lee
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D004148:Dioxolanes / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D010881:Piperidones
chemical_list: D004148:Dioxolanes; D051547:Heme Oxygenase-1; D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; C495635:NFE2L2 protein, human; C496541:HMOX1 protein, human; C498077:piperlongumine; D010881:Piperidones
keywords: HO-1; Nrf2; apoptosis; breast cancer; piperlongumine