Overexpression of salivary-type amylase reduces the sensitivity to bortezomib in multiple myeloma cells.
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.
Division of Hematology, Department of Internal Medicine, Aichi Medical University, 1, 1 Karimata, Yazako, Nagakute, Aichi, 480-1195, Japan.
Shohei
S
Mizuno
Division of Hematology, Department of Internal Medicine, Aichi Medical University, 1, 1 Karimata, Yazako, Nagakute, Aichi, 480-1195, Japan. hanamura@aichi-med-u.ac.jp.
Ichiro
I
Hanamura
Department of Biochemistry, Aichi Medical University, Nagakute, Aichi, Japan.
Akinobu
A
Ota
Department of Biochemistry, Aichi Medical University, Nagakute, Aichi, Japan.
Sivasundaram
S
Karnan
Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.
Tomoko
T
Narita
Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.
Masaki
M
Ri
Division of Hematology, Department of Internal Medicine, Aichi Medical University, 1, 1 Karimata, Yazako, Nagakute, Aichi, 480-1195, Japan.
Motonori
M
Mizutani
Division of Hematology, Department of Internal Medicine, Aichi Medical University, 1, 1 Karimata, Yazako, Nagakute, Aichi, 480-1195, Japan.
Mineaki
M
Goto
Division of Hematology, Department of Internal Medicine, Aichi Medical University, 1, 1 Karimata, Yazako, Nagakute, Aichi, 480-1195, Japan.
Mayuko
M
Gotou
Division of Hematology, Department of Internal Medicine, Aichi Medical University, 1, 1 Karimata, Yazako, Nagakute, Aichi, 480-1195, Japan.
Norikazu
N
Tsunekawa
Department of Hematology, Daiyukai General Hospital, Ichinomiya, Aichi, Japan.
Masato
M
Shikami
Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.
Shinsuke
S
Iida
Department of Biochemistry, Aichi Medical University, Nagakute, Aichi, Japan.
Yoshitaka
Y
Hosokawa
Department of Internal Medicine, Toyama Hospital, Tsu, Mie, Japan.
Hiroshi
H
Miwa
Department of Tumor Immunology, Aichi Medical University, Nagakute, Aichi, Japan.
Ryuzo
R
Ueda
Division of Hematology, Department of Internal Medicine, Aichi Medical University, 1, 1 Karimata, Yazako, Nagakute, Aichi, 480-1195, Japan.
Masakazu
M
Nitta
Division of Hematology, Department of Internal Medicine, Aichi Medical University, 1, 1 Karimata, Yazako, Nagakute, Aichi, 480-1195, Japan.
Akiyoshi
A
Takami
D000681:Amylases / Q000096:biosynthesis*; D000818:Animals; D000069286:Bortezomib / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D011518:Proto-Oncogene Proteins; C090851:TCL1A protein, human; D000069286:Bortezomib; D051057:Proto-Oncogene Proteins c-akt; D000681:Amylases
Amylase; Bortezomib; Lenalidomide; Myeloma; Transfectant