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.

Piperlongumine rapidly induces the death of human pancreatic cancer cells mainly through the induction of ferroptosis

“…Erastin increases the mRNA levels of heme oxygenase-1 in HT-1080 fibrosarcoma cells (37). Lee et al reported that heme oxygenase-1 influenced the differential responses of breast cancer and normal cells to PL (38). We found that CN-A (15 µg/ml) or PL (6 or 8 µM) markedly increased the mRNA levels of heme oxygenase-1 for 16 h in the PANC-1 cells (data not shown).…”

Simvastatin induces heme oxygenase-1 via NF-E2-related factor 2 (Nrf2) activation through ERK and PI3K/Akt pathway in colon cancer

“…On the other hand, pro-apoptotic and anti-proliferative functions of HO-1 have been reported in prostate cancer [33], breast cancer [34] and oral cancer [35], although the mechanism of action is not known. In a previous study, HO-1 determines the differential response of breast cancer and normal cells to piperlongumine [36]. This study suggested that HO-1 has an anti-tumor function in cancer cells, but cytoprotective functions in normal cells.…”

Transcriptome Analysis of Piperlongumine-Treated Human Pancreatic Cancer Cells Reveals Involvement of Oxidative Stress and Endoplasmic Reticulum Stress Pathways

“…30,31 Recently, HMOX-1 expression was shown to be elevated by PL in breast cancer cells and a determining factor in the differential response of normal breast cells to PL. 32 Interestingly, PL silenced ATP-binding cassette subfamily B, member 10 (ABCB10) expression. Recent evidence suggests that ABCB10, a regulator of heme synthesis, helps protect against oxidative stress in vivo by peptide export and/or other molecules specifically regulating antioxidant function and/or avoiding mitochondrial oxidative damage.…”