PMID- 31888545 OWN - NLM STAT- MEDLINE DCOM- 20200505 LR - 20200505 IS - 1471-2407 (Electronic) IS - 1471-2407 (Linking) VI - 19 IP - 1 DP - 2019 Dec 30 TI - Elucidating the expression and function of Numbl during cell adhesion-mediated drug resistance (CAM-DR) in multiple myeloma (MM). PG - 1269 LID - 10.1186/s12885-019-6446-y [doi] LID - 1269 AB - BACKGROUND: Cell adhesion-mediated drug resistance (CAM-DR) is a major clinical problem that prevents successful treatment of multiple myeloma (MM). In particular, the expression levels of integrin beta1 and its sub-cellular distribution (internalization and trafficking) are strongly associated with CAM-DR development. METHODS: Development of an adhesion model of established MM cell lines and detection of Numbl and Integrinbeta1 expression by Western Blot analysis. The interaction between Numbl and Integrinbeta1 was assessed by a co-immunoprecipitation (CO-IP) method. Calcein AM assay was performed to investigate the levels of cell adhesion. Finally, the extent of CAM-DR in myeloma cells was measured using cell viability assay and flow cytometry analysis. RESULTS: Our preliminary date suggest that Numbl is differentially expressed in a cell adhesion model of MM cell lines. In addition to binding to the phosphotyrosine-binding (PTB) domain, the carboxyl terminal of Numbl can also interact with integrin beta1 to regulate the cell cycle by activating the pro-survival PI3K/AKT signaling pathway. This study intends to verify and elucidate the interaction between Numbl and integrin beta1 and its functional outcome on CAM-DR. We have designed and developed a CAM-DR model using MM cells coated with either fibronectin or bone marrow stromal cells. We assessed whether Numbl influences cell-cycle progression and whether it, in turn, contributes to activation of PI3K/AKT signal pathway through the adjustment of its carboxyl end. Finally, we showed that the interaction of Numbl with integrin beta1 promotes the formation of CAM-DR in MM cells. CONCLUSIONS: Our findings elucidated the specific molecular mechanisms of CAM-DR induction and confirmed that Numbl is crucial for the development of CAM-DR in MM cells. FAU - Huang, Yuejiao AU - Huang Y AD - Department of Oncology, Nantong University Cancer Hospital, Nantong, Jiangsu, 226001, People's Republic of China. FAU - Huang, Xianting AU - Huang X AD - Department of Oncology center, Jiangsu Jiangyin People's Hospital, Jiangyin, Jiangsu, 214400, People's Republic of China. FAU - Cheng, Chun AU - Cheng C AD - Department of Pathogenic Biology, School of Medicine, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China. FAU - Xu, Xiaohong AU - Xu X AD - Department of Oncology, Nantong University Cancer Hospital, Nantong, Jiangsu, 226001, People's Republic of China. FAU - Liu, Hong AU - Liu H AD - Department of Hematology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, People's Republic of China. FAU - Yang, Xiaojing AU - Yang X AD - Department of Pathogenic Biology, School of Medicine, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China. FAU - Yao, Li AU - Yao L AD - Department of Immunology, Medical College of Jiangnan University, Wuxi, Jiangsu, 214122, People's Republic of China. FAU - Ding, Zongmei AU - Ding Z AD - Department of Pathogenic Biology, School of Medicine, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China. FAU - Tang, Jie AU - Tang J AD - Department of Pathogenic Biology, School of Medicine, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China. FAU - He, Song AU - He S AD - Department of Pathology, Nantong University Cancer Hospital, Nantong, Jiangsu, 226001, People's Republic of China. hesong2009@126.com. FAU - Wang, Yuchan AU - Wang Y AD - Department of Pathogenic Biology, School of Medicine, Nantong University, Nantong, Jiangsu, 226001, People's Republic of China. ychan.wang@163.com. LA - eng GR - 81600158/National Natural Science Foundation of China/ GR - 81670196/National Natural Science Foundation of China/ GR - WQ2016057/National Funds for Distinguished Young Scientists of Nantong/ GR - BK20160060/Natural Science Foundation of Jiangsu Province/ GR - 16KJ320004/Major Research of Natural Science Foundation for Colleges and Universities in Jiangsu Province/ GR - 2015-SWYY-021/Six Talent Peaks Project in Jiangsu Province/ PT - Journal Article DEP - 20191230 PL - England TA - BMC Cancer JT - BMC cancer JID - 100967800 RN - 0 (Integrin beta1) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (NUMBL protein, human) RN - 7S5I7G3JQL (Dexamethasone) RN - 80168379AG (Doxorubicin) RN - BZ114NVM5P (Mitoxantrone) SB - IM MH - Cell Adhesion MH - Cell Cycle MH - Cell Line MH - Cell Survival MH - Dexamethasone/*therapeutic use MH - Doxorubicin/*therapeutic use MH - Drug Resistance, Neoplasm/genetics MH - Gene Expression MH - Humans MH - Integrin beta1/*metabolism MH - Intracellular Signaling Peptides and Proteins/genetics/*metabolism MH - Mitoxantrone/*therapeutic use MH - Multiple Myeloma/*drug therapy MH - Phosphatidylinositol 3-Kinases/metabolism MH - Protein Binding MH - Signal Transduction MH - Stromal Cells/*pathology PMC - PMC6937660 OTO - NOTNLM OT - Integrin beta1, CAM-DR OT - MM OT - Numbl COIS- The authors declare that they have no competing interests. EDAT- 2020/01/01 06:00 MHDA- 2020/05/06 06:00 PMCR- 2019/12/30 CRDT- 2020/01/01 06:00 PHST- 2019/04/14 00:00 [received] PHST- 2019/12/09 00:00 [accepted] PHST- 2020/01/01 06:00 [entrez] PHST- 2020/01/01 06:00 [pubmed] PHST- 2020/05/06 06:00 [medline] PHST- 2019/12/30 00:00 [pmc-release] AID - 10.1186/s12885-019-6446-y [pii] AID - 6446 [pii] AID - 10.1186/s12885-019-6446-y [doi] PST - epublish SO - BMC Cancer. 2019 Dec 30;19(1):1269. doi: 10.1186/s12885-019-6446-y.