title: Cell adhesion to fibronectin down-regulates the expression of Spy1 and contributes to drug resistance in multiple myeloma cells.
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 p27(Kip1) 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 p27(Kip1) when RPMI 8226 cells bound FN. Spy1 overexpression promoted p27(Kip1) phosphorylation at T187, then induced the p27(Kip1) degradation in the adhesion model. In addition, increasing p27(Kip1) level or disturbing p27(Kip1) 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 p27(Kip1). Our findings provide a rational framework for further development of Spy1 as a novel target for MM therapy.
authors.affiliation: Jiangsu Institute of Hematology, The First Affiliated Hospital, Soochow University, Suzhou, Jiangsu, China.
authors.forename: Min
authors.initials: M
authors.lastname: Fei
authors.forename: Qinglei
authors.initials: Q
authors.lastname: Hang
authors.forename: Sicong
authors.initials: S
authors.lastname: Hou
authors.forename: Changgeng
authors.initials: C
authors.lastname: Ruan
mesh_terms: D017209:Apoptosis / Q000235:genetics; D002448:Cell Adhesion / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005353:Fibronectins / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D009101:Multiple Myeloma / Q000235:genetics* / Q000378:metabolism*; D010766:Phosphorylation; D059748:Proteolysis
chemical_list: D018797:Cell Cycle Proteins; D005353:Fibronectins; C486530:SPDYA protein, human; D050760:Cyclin-Dependent Kinase Inhibitor p27
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