Silencing of CKIP-1 promotes tumor proliferation and cell adhesion-mediated drug resistance via regulating AKT activity in non-Hodgkin's lymphoma.

Casein kinase 2 interacting protein-1 (CKIP-1; also known as PLEKHO1) is involved in regulating many processes such as cell proliferation, differentiation and apoptosis. CKIP-1 also plays an important role in many types of cancer, such as colon, breast cancer and human osteosarcoma. In the present study, we found that CKIP-1 was reversely associated with the proliferation of non-Hodgkin's lymphoma (NHL) and cell adhesion mediated drug resistance (CAM-DR). We demonstrated that knockdown of CKIP-1 promoted the proliferation of NHL cells through interacting with Akt and suppressing Akt phosphorylation. In addition, adhesion of lymphoma cells to fibronectin or stroma cells (HS-5 cells) decreased CKIP-1 expression, which led to the upregulation of Akt phosphorylation. Importantly, we showed that the phosphorylation of Akt was correlated with CAM-DR phenotype in NHL cells. Taken together, the present study shed new light on the molecular mechanism of CAM-DR in NHL and targeting CKIP-1 may be a novel therapeutic target for NHL.

[1]  Anna Bowzyk Al-Naeeb,et al.  Non-Hodgkin lymphoma , 2018, British Medical Journal.

[2]  Liewei Wang,et al.  HEATR1 Negatively Regulates Akt to Help Sensitize Pancreatic Cancer Cells to Chemotherapy. , 2016, Cancer research.

[3]  Gong Yang,et al.  RY-2f, an isoflavone analog, overcomes cisplatin resistance to inhibit ovarian tumorigenesis via targeting the PI3K/AKT/mTOR signaling pathway , 2015, Oncotarget.

[4]  Jia-xin Yang,et al.  The PI3K/AKT/mTOR pathway is a potential predictor of distinct invasive and migratory capacities in human ovarian cancer cell lines , 2015, Oncotarget.

[5]  A. Rust,et al.  BRAF inhibitor resistance mediated by the AKT pathway in an oncogenic BRAF mouse melanoma model , 2015, Proceedings of the National Academy of Sciences.

[6]  L. Liu,et al.  CKIP-1 acts as a colonic tumor suppressor by repressing oncogenic Smurf1 synthesis and promoting Smurf1 autodegradation , 2014, Oncogene.

[7]  F. He,et al.  CKIP-1 regulates macrophage proliferation by inhibiting TRAF6-mediated Akt activation , 2014, Cell Research.

[8]  H. Nakayama,et al.  Overexpression of fibronectin confers cell adhesion-mediated drug resistance (CAM-DR) against 5-FU in oral squamous cell carcinoma cells. , 2014, International journal of oncology.

[9]  J. Bradner,et al.  A microenvironment-mediated c-Myc/miR-548m/HDAC6 amplification loop in non-Hodgkin B cell lymphomas. , 2013, The Journal of clinical investigation.

[10]  S. Maxwell,et al.  Non-Hodgkin’s B-cell lymphoma: Advances in molecular strategies targeting drug resistance , 2013, Experimental biology and medicine.

[11]  Yu Jiang,et al.  Silencing of Human Phosphatidylethanolamine-Binding Protein 4 Enhances Rituximab-Induced Death and Chemosensitization in B-Cell Lymphoma , 2013, PloS one.

[12]  F. Mao,et al.  Interaction with Cyclin H/Cyclin-dependent Kinase 7 (CCNH/CDK7) Stabilizes C-terminal Binding Protein 2 (CtBP2) and Promotes Cancer Cell Migration* , 2013, The Journal of Biological Chemistry.

[13]  M. Fukayama,et al.  Expression of multidrug resistance 1 gene in B‐cell lymphomas: association with follicular dendritic cells , 2013, Histopathology.

[14]  F. He,et al.  CKIP-1: A scaffold protein and potential therapeutic target integrating multiple signaling pathways and physiological functions , 2013, Ageing Research Reviews.

[15]  A. K. Church,et al.  Bone marrow stromal cells protect lymphoma B‐cells from rituximab‐induced apoptosis and targeting integrin α‐4‐β‐1 (VLA‐4) with natalizumab can overcome this resistance , 2011, British journal of haematology.

[16]  T. Tsuruo,et al.  Casein kinase 2-interacting protein-1, a novel Akt pleckstrin homology domain-interacting protein, down-regulates PI3K/Akt signaling and suppresses tumor growth in vivo. , 2007, Cancer research.

[17]  J. Tao,et al.  Bone marrow stromal cells prevent apoptosis of lymphoma cells by upregulation of anti-apoptotic proteins associated with activation of NF-κB (RelB/p52) in non-Hodgkin's lymphoma cells , 2007, Leukemia.

[18]  F. He,et al.  The PH domain containing protein CKIP-1 binds to IFP35 and Nmi and is involved in cytokine signaling. , 2007, Cellular signalling.

[19]  J. Cooper,et al.  The Role of CKIP-1 in Cell Morphology Depends on Its Interaction with Actin-capping Protein* , 2006, Journal of Biological Chemistry.

[20]  W. Dalton,et al.  Cell adhesion induces p27Kip1-associated cell-cycle arrest through down-regulation of the SCFSkp2 ubiquitin ligase pathway in mantle-cell and other non-Hodgkin B-cell lymphomas. , 2006, Blood.

[21]  W. Dalton,et al.  Tumor microenvironment and drug resistance in hematologic malignancies. , 2006, Blood reviews.

[22]  Yun-ping Zhu,et al.  CKIP-1 recruits nuclear ATM partially to the plasma membrane through interaction with ATM. , 2006, Cellular signalling.

[23]  Yiling Lu,et al.  Exploiting the PI3K/AKT Pathway for Cancer Drug Discovery , 2005, Nature Reviews Drug Discovery.

[24]  Yun-ping Zhu,et al.  Role for the pleckstrin homology domain‐containing protein CKIP‐1 in AP‐1 regulation and apoptosis , 2005, The EMBO journal.

[25]  W. Dalton,et al.  Adhesion to fibronectin via β1 integrins regulates p27kip1 levels and contributes to cell adhesion mediated drug resistance (CAM-DR) , 2000, Oncogene.

[26]  H Stein,et al.  A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. , 1994, Blood.

[27]  R. Wei,et al.  CKIP-1 acts as a colonic tumor suppressor by repressing oncogenic Smurf1 synthesis and promoting Smurf1 autodegradation , 2014, Oncogene.