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Overexpression of salivary-type amylase reduces the sensitivity to bortezomib in multiple myeloma cells

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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.

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Acknowledgments

The authors would like to thank Ms. A. Nakamura for her valuable secretarial assistance and Brian Quinn for his editorial assistance. This study was supported by grants from the Ministry of Health, Labour and Welfare of Japan, the Ministry of Education, Culture, Sports and Technology of Japan, the SENSHIN Medical Research Foundation (Osaka, Japan), the Aichi Cancer Research Foundation (Nagoya, Japan), and the 24th General Assembly of the Japanese Association of Medical Sciences (Nagoya, Japan). The funders played no role in the study design, data collection and analysis, the decision to publish or the preparation of the manuscript.

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Authors and Affiliations

  1. Division of Hematology, Department of Internal Medicine, Aichi Medical University, 1, 1 Karimata, Yazako, Nagakute, Aichi, 480-1195, Japan

    Shohei Mizuno, Ichiro Hanamura, Motonori Mizutani, Mineaki Goto, Mayuko Gotou, Norikazu Tsunekawa, Masakazu Nitta & Akiyoshi Takami

  2. Department of Biochemistry, Aichi Medical University, Nagakute, Aichi, Japan

    Akinobu Ota, Sivasundaram Karnan & Yoshitaka Hosokawa

  3. Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan

    Tomoko Narita, Masaki Ri & Shinsuke Iida

  4. Department of Hematology, Daiyukai General Hospital, Ichinomiya, Aichi, Japan

    Masato Shikami

  5. Department of Internal Medicine, Toyama Hospital, Tsu, Mie, Japan

    Hiroshi Miwa

  6. Department of Tumor Immunology, Aichi Medical University, Nagakute, Aichi, Japan

    Ryuzo Ueda

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  1. Shohei Mizuno
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  2. Ichiro Hanamura
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Correspondence to Ichiro Hanamura.

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12185_2015_1859_MOESM1_ESM.pptx

Supplementary material 1 Supplementary Fig. 1. Representative histology (H&E) and immunohistochemistry (CD138) of 8226/AMY1 xenograft tumor (A), liver (B), bone marrow (C) and spleen (D) in xenotransplanted mice. There was no apparent infiltration of 8226/AMY1 cells into these organs in xenotransplanted mice. Supplementary Fig. 2. Array comparative genomic hybridization analysis of the innate amylase-producing human myeloma cell lines (FR4 and KMS12PE). Data indicated no alterations of the AMY1 copy number in these cell lines. (PPTX 1753 kb)

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Mizuno, S., Hanamura, I., Ota, A. et al. Overexpression of salivary-type amylase reduces the sensitivity to bortezomib in multiple myeloma cells. Int J Hematol 102, 569–578 (2015). https://doi.org/10.1007/s12185-015-1859-0

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  • DOI: https://doi.org/10.1007/s12185-015-1859-0

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