Neuroglobin overexpression induced by the 17β-Estradiol-Estrogen receptor-α Pathway reduces the sensitivity of MCF-7 Breast cancer cell to paclitaxel.
Although paclitaxel (Taxol) is an active chemotherapeutic agent for the treatment of breast cancer, not all breast tumors are sensitive to this drug. In particular, there is a wide agreement on the low sensitivity of estrogen receptor (ER) α-positive breast cancer to paclitaxel treatment. However, the ERα-based insensitivity to paclitaxel is still elusive. Here, the effect of the E2/ERα-dependent upregulation of neuroglobin (NGB), an antiapoptotic globin, on the reduced sensitivity of breast cancer cells to paclitaxel-induced apoptosis has been evaluated in ERα-containing MCF-7 cells. The E2 pretreatment enhances the ERα activity and significantly impairs paclitaxel-induced apoptosis as evaluated by Annexin V assay and PARP-1 cleavage. NGB displays a pivotal role in the E2/ERα-induced antiapoptotic pathway to abrogate paclitaxel-induced cell death in stable NGB-silenced MCF-7 cell clones. Moreover, in the absence of the active ERα, paclitaxel significantly reduces the NGB cell content. In conclusion, these results highlight the involvement of ERα activation and of E2/ERα-dependent NGB upregulation in the insensitivity of MCF-7 to paclitaxel. These novel findings could have important implications in the development of targeted therapeutics for overcoming paclitaxel insensitivity in ERα-positive human breast cancer. © 2016 IUBMB Life, 68(8):645-651, 2016.
Department of Science, Roma Tre University, Roma, Italy.
Marco
M
Fiocchetti
Department of Science, Roma Tre University, Roma, Italy.
Manuela
M
Cipolletti
Department of Science, Roma Tre University, Roma, Italy.
Stefano
S
Leone
Department of Science, Roma Tre University, Roma, Italy.|Interdepartmental Laboratory of Electron Microscopy, Roma Tre University, Roma, Italy.
Paolo
P
Ascenzi
Department of Science, Roma Tre University, Roma, Italy.
Maria
M
Marino
D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004958:Estradiol / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005914:Globins / Q000235:genetics*; D006801:Humans; D061986:MCF-7 Cells; D009419:Nerve Tissue Proteins / Q000235:genetics*; D000078787:Neuroglobin; D017239:Paclitaxel / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects
C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D009419:Nerve Tissue Proteins; D000078787:Neuroglobin; D004958:Estradiol; D005914:Globins; D017239:Paclitaxel
MCF-7 cells; apoptosis; chemotherapy; estrogen receptor-α; neuroglobin; paclitaxel