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Heme oxygenase-1 determines the differential response of breast cancer and normal cells to piperlongumine.

Lee HN, Jin HO, Park JA, Kim JH, Kim JY, Kim B, Kim W, Hong SE, Lee YH, Chang YH, Hong SI, Hong YJ, Park IC, Surh YJ, Lee JK - Mol. Cells (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, Seoul 139-709, Korea.

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.

No MeSH data available.


Related in: MedlinePlus

The proposed mechanism underlying a cancer cell-selective killing effect of piperlongumine. Through direct binding, piperlongumine induces thiol modification of Keap1, thereby allowing nuclear translocation of Nrf2 and subsequent upregulation of HO-1 expression in normal and cancer cells. HO-1 determines the differential response of breast normal cells and cancer cells to piperlongumine, resulting in selective killing of cancer cells.
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f6-molce-38-4-327: The proposed mechanism underlying a cancer cell-selective killing effect of piperlongumine. Through direct binding, piperlongumine induces thiol modification of Keap1, thereby allowing nuclear translocation of Nrf2 and subsequent upregulation of HO-1 expression in normal and cancer cells. HO-1 determines the differential response of breast normal cells and cancer cells to piperlongumine, resulting in selective killing of cancer cells.

Mentions: In conclusion, the results from our present study demonstrate a novel mechanism underlying a cancer cell-selective killing effect of piperlongumine (Fig. 6). We suggest that HO-1 is a key factor determining the differential response of breast normal cells and cancer cells to piperlongumine, and the thiol modification of Keap1 is responsible for piperlongumine-induced activation of Nrf2 signaling and HO-1 expression.


Heme oxygenase-1 determines the differential response of breast cancer and normal cells to piperlongumine.

Lee HN, Jin HO, Park JA, Kim JH, Kim JY, Kim B, Kim W, Hong SE, Lee YH, Chang YH, Hong SI, Hong YJ, Park IC, Surh YJ, Lee JK - Mol. Cells (2015)

The proposed mechanism underlying a cancer cell-selective killing effect of piperlongumine. Through direct binding, piperlongumine induces thiol modification of Keap1, thereby allowing nuclear translocation of Nrf2 and subsequent upregulation of HO-1 expression in normal and cancer cells. HO-1 determines the differential response of breast normal cells and cancer cells to piperlongumine, resulting in selective killing of cancer cells.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4400307&req=5

f6-molce-38-4-327: The proposed mechanism underlying a cancer cell-selective killing effect of piperlongumine. Through direct binding, piperlongumine induces thiol modification of Keap1, thereby allowing nuclear translocation of Nrf2 and subsequent upregulation of HO-1 expression in normal and cancer cells. HO-1 determines the differential response of breast normal cells and cancer cells to piperlongumine, resulting in selective killing of cancer cells.
Mentions: In conclusion, the results from our present study demonstrate a novel mechanism underlying a cancer cell-selective killing effect of piperlongumine (Fig. 6). We suggest that HO-1 is a key factor determining the differential response of breast normal cells and cancer cells to piperlongumine, and the thiol modification of Keap1 is responsible for piperlongumine-induced activation of Nrf2 signaling and HO-1 expression.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, Seoul 139-709, Korea.

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.

No MeSH data available.


Related in: MedlinePlus