[Proteasome inhibitor induces apoptosis and influences the expression of Notch1 and NF-kappaB in multiple myeloma RPMI8226 cells].
The occurrence and development of Multiple myeloma (MM) are closely related to bone marrow microenvironment in which many signal pathways were involved. Notch signal plays an important role in regulating hematopoietic cells proliferation and differentiation in hemopoietic microenvironment, especially Notch1 has close touch with the occurrence and development of neoplastic hematologic disorders. MM deeply depends on NF-kappaB, and the latter has something to do with oncogenesis, metastasis, proliferation, apoptosis and drug resistance of tumor cells. NF-kappaB2 family has been confirmed as one of target genes of Notch signal. Bortezomib as representative of proteasome inhibitors has been licensed by FDA in treating refractory and relapsing MM, but the mechanism of bortezomib inducing cells apoptosis is not yet clear. This study was purposed to investigate the effects of bortezomib inducing cell apoptosis and influencing the erpression of Notch1 and NF-kappaB in MM RPMI 8226 cells. The effect of bortezomib on apoptosis of MM RPMI8226 cells was assayed by transmission electron microscopy, flow cytometry and TUNEL; the expressions of Notch 1 and NF-kappaB in apoptotic RPMI8226 cells were detected by RT-PCR and immunofluorescence cytochemical staining respectively. The results showed that Notch1 and NF-kappaB highly expressed in RPMI 8226 cells. With the increase of bortezomib concentration, the typical apoptosis features of RPMI8226 cells were observed, the expressions of Notch1 and the expression of NF-kappaB decreased in nuclei and increased in cytoplasm. These changes had significant difference from control after concentration of bortezomib was raised to a certain degree. It is concluded that Notch1 and NF-kappaB signaling pathways participate in bortezomib-inducing RPMI8226 cell apoptosis and there may be some correlation between the Notch 1 and NF-kappaB signaling pathways, indicating that Notch 1 signal may be a latent target in treating MM. This study provides a certain experimental basis for research and development of new drugs.
Department of Hematology, The First Hospital, Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China.
Hui
H
Wang
Xin
X
Liu
Bo
B
Xu
D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D006801:Humans; D009101:Multiple Myeloma / Q000473:pathology*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D001897:Boronic Acids; D016328:NF-kappa B; C497761:NOTCH1 protein, human; D011480:Protease Inhibitors; D011719:Pyrazines; D051881:Receptor, Notch1; D000069286:Bortezomib