Drug-resistant breast carcinoma (MCF-7) cells are paradoxically sensitive to apoptosis

• Published in: Journal of cellular physiology 2004-08, Vol.200 (2), p.223-234
• Main Authors: Chen, Jack S.K., Konopleva, Marina, Andreeff, Michael, Multani, Asha S., Pathak, Sen, Mehta, Kapil
• Format: Article
• Language: English
• Subjects: Antibiotics, Antineoplastic - therapeutic use; Apoptosis - drug effects; Blotting, Western; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Calcimycin - pharmacology; Carcinoma - pathology; Caspase 3; Caspase 8; Caspases - metabolism; Cell Line, Tumor; Cytochromes c - secretion; Doxorubicin - therapeutic use; Drug Resistance, Neoplasm; Enzyme Activation; Enzyme Inhibitors - pharmacology; Female; Humans; Ionophores - pharmacology; Membrane Potentials - drug effects; Mitochondria - drug effects; Mitochondria - physiology; Staurosporine - pharmacology
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.20014

The purpose of this study was to determine whether expression of tissue transglutaminase (TG2) and caspase‐3 proteins in drug‐resistant breast carcinoma MCF‐7/DOX cells would render these cells selectively susceptible to apoptotic stimuli. Despite high resistance to multidrug resistance (MDR)‐related drug, doxorubicin (≥150‐fold), the MCF‐7/DOX cells were extremely sensitive to apoptotic stimuli. Thus, calcium ionophore, A23187 (A23187) and the protein kinase C inhibitor staurosporine (STS) each induced rapid and time‐dependent apoptosis in MCF‐7/DOX cells. The apoptosis induced by either agent was accompanied by caspase‐3 activation and other downstream changes that are typical of cells undergoing apoptosis. The alterations upstream of caspase‐3 activation, however, such as loss in mitochondrial membrane potential (ΔΨ), release of cytochrome c, and activation of caspase‐8, and caspase‐9, were detected only in STS‐treated cells. The A12387 failed to induce any of the caspase‐3 upstream changes, implying that A23187‐induced apoptosis may utilize one or more novel upstream pathways leading to the activation of caspase 3. In summary, these data demonstrate that MCF‐7/DOX cells are much more sensitive to apoptotic stimuli than previously thought and that A23187‐induced apoptosis may involve some novel, yet unidentified, upstream pathway that leads to the activation of caspase‐3 and other downstream events. © 2004 Wiley‐Liss, Inc.