Cytoprotective effects of ferritin on doxorubicin-induced breast cancer cell death.
Ferritin is a major iron storage protein and essential for iron homeostasis. It has a wide range of functions in the body including iron delivery, immunosuppression, angiogenesis, and cell proliferation. Ferritin is overexpressed in many cancer cells, but its precise role in cancer is unclear. In the present study, we examined the functional roles of ferritin in protecting the MCF-7 breast cancer cell line against treatment with the chemotherapeutic agent doxorubicin. The effects of ferritin (human liver ferritin) and doxorubicin on the human MCF-7 breast cancer cell line were evaluated using the cell viability assay. The impact of decreasing ferritin light chain (FTL) and ferritin heavy chain (FTH) expression on doxorubicin sensitivity was assessed using siRNA. Reactive oxygen species (ROS) was also measured using the fluorescence probe CM-H2DCFDA. The mechanism of modulated chemosensitivity was evaluated by western blot analysis. Ferritin treatment activated MCF-7 cell proliferation in a concentration- and time-dependent manner. While treatment with doxorubicin alone significantly increased intracelullar ROS production, the addition of ferritin decreased this ROS formation, thereby reducing doxorubicin‑induced MCF-7 cell death. The inhibition of FTL and FTH by siRNA sensitized cells to doxorubicin. Treatment with doxorubicin alone significantly induced the cell cycle‑dependent kinase inhibitor protein p21, whereas ferritin reduced p21 expression. Thus, ferritin plays a critical role in protecting MCF-7 cells against the chemotherapeutic drug doxorubicin. A targeted reduction of ferritin may be a useful strategy for overcoming chemoresistance in breast cancer.
Faculty of Medicine, Mahasarakham University, Muang, Mahasarakham 44000, Thailand.
Benjaporn
B
Buranrat
Department of Neurosurgery, The Pennsylvania State University Hershey Medical Center, Hershey, PA 17033, USA.
James R
JR
Connor
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001052:Apoferritins / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D017209:Apoptosis; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D017382:Reactive Oxygen Species / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D017382:Reactive Oxygen Species; D004317:Doxorubicin; D001052:Apoferritins