Abstract
Expression of CD45 is quite variable in human myeloma cells and cell lines, such as U266, and CD45+ U266 proliferates in response to a growth factor, interleukin-6. Here, we show that CD45+ myeloma cell lines were more sensitive to various apoptotic stimuli, such as oxidative stress and endoplasmic reticulum (ER)-stress, than CD45− cells. Reactive oxygen species and calcium ion seemed to be involved in the susceptibility to apoptosis of CD45+ U266. The activation of the src family kinases associated with CD45 phosphatase played an important role in the augmented apoptosis in CD45+ U266 by oxidative stress. These results indicate that the CD45-expression renders myeloma cells competent for not only mitogenic but also apoptotic stimuli, resulting in either proliferation or apoptosis of CD45+ myeloma cells dependently upon the circumstantial stimuli. Furthermore, voltage-dependent anion channel (VDAC) 1 was identified as a gene highly expressed in CD45+ U266 by cDNA subtraction. The increased expression of VDAC1 seemed to augment the sensitivity to the ER-stress because the VDAC1-transfected U266 was more susceptible to the thapsigargin-induced apoptosis. Thus, CD45 expression accompanied by the increased VDAC1 expression sensitizes myeloma cells to the various extracellular stimuli that trigger apoptosis via the mitochondrial pathways.
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Acknowledgements
We thank Dr Harumi Suzuki (Yamaguchi University) and Dr Hideki Asaoku (Hiroshima Red Cross Hospital) for providing us a retrovirus vector, pMx-puro and bone marrow aspirates from myeloma patients, respectively. We also thank the Center for Gene Research, Yamaguchi University for DNA sequencing. This work was supported in part by grants from the Ministry of Education, Science, Sports and Culture of Japan, the Ministry of Health, Labour and Welfare of Japan, the Japan Society for the Promotion of Science (JSPS), Mitsubishi Pharma Research Foundation and International Myeloma Foundation. JSPS Postdoctoral Fellowship for Foreign Researchers (P04500) awarded to SA.
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Liu, S., Ishikawa, H., Tsuyama, N. et al. Increased susceptibility to apoptosis in CD45+ myeloma cells accompanied by the increased expression of VDAC1. Oncogene 25, 419–429 (2006). https://doi.org/10.1038/sj.onc.1208982
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DOI: https://doi.org/10.1038/sj.onc.1208982
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