Involvement of Notch-1 signaling in bone marrow stroma-mediated de novo drug resistance of myeloma and other malignant lymphoid cell lines.
The bone marrow (BM) microenvironment plays a critical role in malignant cell growth, patient survival, and response to chemotherapy in hematologic malignancies. However, mechanisms associated with this environmental influence remain unclear. In this study, we investigated the role of Notch family proteins in myeloma and other malignant lymphoid cell line growth and response to chemotherapeutic drugs. All 8 tested cell lines expressed Notch-3 and Notch-4; 7 cell lines expressed Notch-1; and 6 expressed Notch-2 proteins. Interaction with BM stroma (BMS) activated Notch signaling in tumor cells. However, activation of only Notch-1, but not Notch-2, resulted in protection of tumor cells from melphalan- and mitoxantrone-induced apoptosis. This protection was associated with up-regulation of p21(WAF/Cip) and growth inhibition of cells. Overexpression of Notch-1 in Notch-1(-) U266 myeloma cells up-regulated p21 and resulted in protection from drug-induced apoptosis. Thus, this is a first report demonstrating that Notch-1 signaling may be a primary mechanism mediating the BMS influence on hematologic malignant cell growth and survival.
Nefedova
Yulia
Y
H Lee Moffitt Cancer Center, University of South Florida, Tampa, FL 33612, USA.
Cheng
Pingyan
P
Alsina
Melissa
M
Dalton
William S
WS
Gabrilovich
Dmitry I
DI
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells; D002450:Cell Communication; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008232:Lymphoproliferative Disorders / Q000473:pathology; D008565:Membrane Proteins / Q000502:physiology; D009101:Multiple Myeloma / Q000473:pathology*; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface / Q000502:physiology*; D051880:Receptors, Notch; D015398:Signal Transduction; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism*; D014157:Transcription Factors; D015854:Up-Regulation
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D014157:Transcription Factors