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Cell adhesion to fibronectin down-regulates the expression of Spy1 and contributes to drug resistance in multiple myeloma cells

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Abstract

Spy1 is a member of the Speedy/Ringo family, which regulates cell proliferation and survival. Spy1 has been demonstrated to promote the cell-cycle progress through p27Kip1 degradation. Previous investigations have suggested cell adhesion-mediated drug resistance (CAM-DR) in multiple myeloma (MM) is a primary factor for minimal residual disease (MRD) leading to relapse after chemotherapy. However, the precise mechanism remains elusive. In this study, we used MM cell lines to determine whether Spy1 plays a role in CAM-DR. We demonstrated that adhesion of MM cells to fibronectin (FN) decreased Spy1 expression. Overexpression of Spy1 did not affect MM cells adhesion to FN, but did reverse the doxorubicin- or mitoxantrone-induced CAM-DR phenotype. Spy1 protein level was also correlated with reciprocal up-regulation of p27Kip1 when RPMI 8226 cells bound FN. Spy1 overexpression promoted p27Kip1 phosphorylation at T187, then induced the p27Kip1 degradation in the adhesion model. In addition, increasing p27Kip1 level or disturbing p27Kip1 phosphorylation at T187 abolished the CAM-DR reversion when Spy1 was overexpressed. Collectively, our data suggest that Spy1 plays an important role in CAM-DR, which depends on the function of p27Kip1. Our findings provide a rational framework for further development of Spy1 as a novel target for MM therapy.

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Conflict of interest

All the authors declare no conflict of interest.

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Authors and Affiliations

  1. Jiangsu Institute of Hematology, The First Affiliated Hospital, Soochow University, Suzhou, Jiangsu, China

    Min Fei & Changgeng Ruan

  2. Institute of Medical Biotechnology, Soochow University, Suzhou, Jiangsu, China

    Min Fei

  3. Department of Immunology, Medical College of Nantong University, Nantong, 226001, Jiangsu, China

    Qinglei Hang

  4. Division of Regulatory Glycobiology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Pharmaceutical University, Sendai, Miyagi, Japan

    Qinglei Hang

  5. Department of Emergency, Subei People’s Hospital, Clinical Medical College of Yangzhou University, Nantong West Road 98, Yangzhou, 225001, China

    Sicong Hou

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  1. Min Fei
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  2. Qinglei Hang
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  4. Changgeng Ruan
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Correspondence to Changgeng Ruan.

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M. Fei and Q. Hang contributed equally to this work.

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Fei, M., Hang, Q., Hou, S. et al. Cell adhesion to fibronectin down-regulates the expression of Spy1 and contributes to drug resistance in multiple myeloma cells. Int J Hematol 98, 446–455 (2013). https://doi.org/10.1007/s12185-013-1435-4

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  • DOI: https://doi.org/10.1007/s12185-013-1435-4

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