1. Overexpression of salivary-type amylase reduces the sensitivity to bortezomib in multiple myeloma cells
- Author
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Tomoko Narita, Ichiro Hanamura, Masakazu Nitta, Akiyoshi Takami, Ryuzo Ueda, Motonori Mizutani, Shinsuke Iida, Mineaki Goto, Masato Shikami, Mayuko Gotou, Masaki Ri, Hiroshi Miwa, Norikazu Tsunekawa, Yoshitaka Hosokawa, Akinobu Ota, Sivasundaram Karnan, and Shohei Mizuno
- Subjects
medicine.medical_specialty ,Mice, SCID ,Biology ,Gene Expression Regulation, Enzymologic ,Bortezomib ,chemistry.chemical_compound ,Mice ,immune system diseases ,Mice, Inbred NOD ,hemic and lymphatic diseases ,Internal medicine ,Cell Line, Tumor ,Proto-Oncogene Proteins ,medicine ,Animals ,Humans ,Protein kinase B ,Dexamethasone ,Multiple myeloma ,Lenalidomide ,Hematology ,Kinase ,Perifosine ,medicine.disease ,Xenograft Model Antitumor Assays ,Gene Expression Regulation, Neoplastic ,chemistry ,Drug Resistance, Neoplasm ,Amylases ,Cancer research ,Multiple Myeloma ,Proto-Oncogene Proteins c-akt ,medicine.drug - Abstract
Amylase-producing myeloma exhibits refractoriness to chemotherapy and a dismal prognosis. In this study, we established a human myeloma cell line, 8226/AMY1, in which a lentivirally transfected AMY1 gene was stably expressed and explored its biological characteristics. 8226/AMY1 showed a survival advantage over mock control when treated with dexamethasone, bortezomib, and lenalidomide in vitro partly through inhibition of apoptosis induced by these reagents. In a xenograft murine model, 8226/AMY1 showed rapid tumor growth and reduced sensitivity to bortezomib compared with mock. A microarray gene expression analysis identified TCL1A, which functions as a coactivator of the cell survival kinase Akt, differentially up-regulated in 8226/AMY1. The expression of phosphorylated Akt was increased in the 8226/AMY1 cells following bortezomib treatment, but not in the mock cells. In addition, treatment with perifosine, an inhibitor of Akt phosphorylation, enhanced the anti-myeloma effect of bortezomib in the 8226/AMY1 cells. Our data suggest that amylase-producing myeloma reduced the sensitivity to bortezomib in vitro and in vivo, and the up-regulation of TCL1A may influence the drug susceptibility of 8226/AMY1 via the phosphorylation of Akt. These findings provide clues for developing treatment approaches for not only amylase-producing myeloma, but also relapsed and refractory myelomas.
- Published
- 2015