Differential cellular and molecular effects of bortezomib, a proteasome inhibitor, in human breast cancer cells.
The cellular and molecular effects of the proteasome inhibitor bortezomib on breast cancer cells are as yet poorly characterized. Here, in a panel of six breast cancer cell lines, bortezomib reduced viability in a concentration-dependent, time-dependent, and cell line-dependent manner. Proteasome activity was relatively high in two of the three more resistant cell lines. No relationship was observed between bortezomib effects on cell viability and expression/phosphorylation of HER-2, epidermal growth factor receptor (EGFR), AKT, or extracellular signal-regulated kinase 1/2 (ERK1/2). Molecular effects of bortezomib were further studied in SK-BR-3 and BT-474 cells because they share expression of EGFR and overexpression of HER-2 while, in contrast, SK-BR-3 cells were 200-fold more sensitive to this agent. Proteasome activity was inhibited to a similar extent in the two cell lines, and known proteasome substrates accumulated similarly. In SK-BR-3 cells, a marked inhibition of EGFR, HER-2, and AKT phosphorylation was observed at a clinically relevant concentration of bortezomib. In contrast, phosphorylation of Raf/mitogen-activated protein kinase kinase 1/2 (MEK 1/2)/ERK1/2 increased by bortezomib. In BT-474 cells, the effects were much less pronounced. Treatment of SK-BR-3 cells with bortezomib combined with pharmacologic inhibitors of EGFR, phosphatidylinositol 3'-kinase, or MEK resulted in modest or no enhancement of the effects on cell viability. Collectively, these results show that bortezomib has differential cellular and molecular effects in human breast cancer cells. The bortezomib-observed effects on signaling transduction molecules might be relevant to help to design mechanistic-based combination treatments.
Laboratory of Experimental Oncology, Medical Oncology Department, Institut d'Investigacions Biomediques August Pi i Sunyer, Hospital Clinic i Provincial de Barcelona, Barcelona, Spain.
Jordi
J
Codony-Servat
Maria A
MA
Tapia
Marta
M
Bosch
Cristina
C
Oliva
Josep
J
Domingo-Domenech
Begoña
B
Mellado
Mark
M
Rolfe
Jeffrey S
JS
Ross
Pere
P
Gascon
Ana
A
Rovira
Joan
J
Albanell
D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D001943:Breast Neoplasms / Q000201:enzymology*; D018797:Cell Cycle Proteins / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D054638:Dual Specificity Phosphatase 1; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D017874:Immediate-Early Proteins / Q000187:drug effects; D048670:MAP Kinase Kinase 4 / Q000187:drug effects; D020930:MAP Kinase Kinase Kinases / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects; D010749:Phosphoprotein Phosphatases / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D061988:Proteasome Inhibitors; D054645:Protein Phosphatase 1; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects; D017027:Protein Tyrosine Phosphatases / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D011719:Pyrazines / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D048490:raf Kinases / Q000187:drug effects
D001897:Boronic Acids; D000069286:Bortezomib; D018797:Cell Cycle Proteins; D015853:Cysteine Proteinase Inhibitors; D054638:Dual Specificity Phosphatase 1; D066246:ErbB Receptors; D017874:Immediate-Early Proteins; D048670:MAP Kinase Kinase 4; D020930:MAP Kinase Kinase Kinases; D019950:Mitogen-Activated Protein Kinase 1; D010749:Phosphoprotein Phosphatases; D061988:Proteasome Inhibitors; D054645:Protein Phosphatase 1; D017346:Protein Serine-Threonine Kinases; D017027:Protein Tyrosine Phosphatases; D051057:Proto-Oncogene Proteins c-akt; D011719:Pyrazines; D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D048490:raf Kinases; C517019:DUSP1 protein, human