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

Zhu,Xinhua; Ouyang,Yu; Zhong,Fei; Wang,Qiru; Ding,Linlin; Zhang,Peipei; Chen,Lingling; Liu,Hong; He,Song

doi:10.3892/or.2016.5233

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

Authors:
- Xinhua Zhu
- Yu Ouyang
- Fei Zhong
- Qiru Wang
- Linlin Ding
- Peipei Zhang
- Lingling Chen
- Hong Liu
- Song He
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Affiliations: Department of Pathology, Affiliated Cancer Hospital of Nantong University, Nantong, Jiangsu 226361, P.R. China, Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong, Jiangsu 226001, P.R. China, Department of Hematology, Affiliated Hospital of Nantong University, Nantong University, Nantong, Jiangsu 22600, P.R. China
Published online on: November 8, 2016 https://doi.org/10.3892/or.2016.5233
Pages: 622-630

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Abstract

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.

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1	Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, Delsol G, De Wolf-Peeters C, Falini B, Gatter KC, et al: A revised European-American classification of lymphoid neoplasms: A proposal from the International Lymphoma Study Group. Blood. 84:1361–1392. 1994.PubMed/NCBI
2	Maxwell SA and Mousavi-Fard S: Non-Hodgkins B-cell lymphoma: Advances in molecular strategies targeting drug resistance. Exp Biol Med (Maywood). 238:971–990. 2013. View Article : Google Scholar : PubMed/NCBI
3	Shankland KR, Armitage JO and Hancock BW: Non-Hodgkin lymphoma. Lancet. 380:848–857. 2012. View Article : Google Scholar : PubMed/NCBI
4	Yagi K, Yamamoto K, Umeda S, Abe S, Suzuki S, Onishi I, Kirimura S, Fukayama M, Arai A, Kitagawa M, et al: Expression of multidrug resistance 1 gene in B-cell lymphomas: Association with follicular dendritic cells. Histopathology. 62:414–420. 2013. View Article : Google Scholar : PubMed/NCBI
5	Lwin T, Hazlehurst LA, Dessureault S, Lai R, Bai W, Sotomayor E, Moscinski LC, Dalton WS and Tao J: Cell adhesion induces p27^Kip1-associated cell-cycle arrest through down-regulation of the SCF^Skp2 ubiquitin ligase pathway in mantle-cell and other non-Hodgkin B-cell lymphomas. Blood. 110:1631–1638. 2007. View Article : Google Scholar : PubMed/NCBI
6	Lwin T, Zhao X, Cheng F, Zhang X, Huang A, Shah B, Zhang Y, Moscinski LC, Choi YS, Kozikowski AP, et al: A microenvironment-mediated c-Myc/miR-548m/HDAC6 amplification loop in non-Hodgkin B cell lymphomas. J Clin Invest. 123:4612–4626. 2013. View Article : Google Scholar : PubMed/NCBI
7	Mraz M, Zent CS, Church AK, Jelinek DF, Wu X, Pospisilova S, Ansell SM, Novak AJ, Kay NE, Witzig TE, 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. Br J Haematol. 155:53–64. 2011. View Article : Google Scholar : PubMed/NCBI
8	Nie J, Liu L, He F, Fu X, Han W and Zhang L: CKIP-1: A scaffold protein and potential therapeutic target integrating multiple signaling pathways and physiological functions. Ageing Res Rev. 12:276–281. 2013. View Article : Google Scholar : PubMed/NCBI
9	Zhang L, Xing G, Tie Y, Tang Y, Tian C, Li L, Sun L, Wei H, Zhu Y and He F: Role for the pleckstrin homology domain-containing protein CKIP-1 in AP-1 regulation and apoptosis. EMBO J. 24:766–778. 2005. View Article : Google Scholar : PubMed/NCBI
10	Tokuda E, Fujita N, Oh-hara T, Sato S, Kurata A, Katayama R, Itoh T, Takenawa T, Miyazono K and Tsuruo T: 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. Cancer Res. 67:9666–9676. 2007. View Article : Google Scholar : PubMed/NCBI
11	Nie J, Liu L, Xing G, Zhang M, Wei R, Guo M, Li X, Xie P, Li L, He F, et al: CKIP-1 acts as a colonic tumor suppressor by repressing oncogenic Smurf1 synthesis and promoting Smurf1 autodegradation. Oncogene. 33:3677–3687. 2014. View Article : Google Scholar : PubMed/NCBI
12	Vilk G, Saulnier RB, St Pierre R and Litchfield DW: Inducible expression of protein kinase CK2 in mammalian cells. Evidence for functional specialization of CK2 isoforms. J Biol Chem. 274:14406–14414. 1999.
13	Zhang L, Wang Y, Xiao F, Wang S, Xing G, Li Y, Yin X, Lu K, Wei R, Fan J, et al: CKIP-1 regulates macrophage proliferation by inhibiting TRAF6-mediated Akt activation. Cell Res. 24:742–761. 2014. View Article : Google Scholar : PubMed/NCBI
14	Wang Y, Liu F, Mao F, Hang Q, Huang X, He S, Wang Y, Cheng C, Wang H, Xu G, et al: Interaction with cyclin H/cyclin-dependent kinase 7 (CCNH/CDK7) stabilizes C-terminal binding protein 2 (CtBP2) and promotes cancer cell migration. J Biol Chem. 288:9028–9034. 2013. View Article : Google Scholar : PubMed/NCBI
15	Zhang L, Tie Y, Tian C, Xing G, Song Y, Zhu Y, Sun Z and He F: CKIP-1 recruits nuclear ATM partially to the plasma membrane through interaction with ATM. Cell Signal. 18:1386–1395. 2006. View Article : Google Scholar : PubMed/NCBI
16	Canton DA, Olsten ME, Niederstrasser H, Cooper JA and Litchfield DW: The role of CKIP-1 in cell morphology depends on its interaction with actin-capping protein. J Biol Chem. 281:36347–36359. 2006. View Article : Google Scholar : PubMed/NCBI
17	Hennessy BT, Smith DL, Ram PT, Lu Y and Mills GB: Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov. 4:988–1004. 2005. View Article : Google Scholar : PubMed/NCBI
18	Liu T, Fang Y, Zhang H, Deng M, Gao B, Niu N, Yu J, Lee S, Kim J, Qin B, et al: HEATR1 negatively regulates Akt to help sensitize pancreatic cancer cells to chemotherapy. Cancer Res. 76:572–581. 2016. View Article : Google Scholar : PubMed/NCBI
19	Perna D, Karreth FA, Rust AG, Perez-Mancera PA, Rashid M, Iorio F, Alifrangis C, Arends MJ, Bosenberg MW, Bollag G, et al: BRAF inhibitor resistance mediated by the AKT pathway in an oncogenic BRAF mouse melanoma model. Proc Natl Acad Sci USA. 112:E536–E545. 2015. View Article : Google Scholar : PubMed/NCBI
20	Hazlehurst LA, Damiano JS, Buyuksal I, Pledger WJ and Dalton WS: Adhesion to fibronectin via β1 integrins regulates p27^kip1 levels and contributes to cell adhesion mediated drug resistance (CAM-DR). Oncogene. 19:4319–4327. 2000. View Article : Google Scholar : PubMed/NCBI
21	Lwin T, Hazlehurst LA, Li Z, Dessureault S, Sotomayor E, Moscinski LC, Dalton WS and Tao J: Bone marrow stromal cells prevent apoptosis of lymphoma cells by upregulation of anti-apoptotic proteins associated with activation of NF-kappaB (RelB/p52) in non-Hodgkins lymphoma cells. Leukemia. 21:1521–1531. 2007. View Article : Google Scholar : PubMed/NCBI
22	Zhang L, Tang Y, Tie Y, Tian C, Wang J, Dong Y, Sun Z and He F: The PH domain containing protein CKIP-1 binds to IFP35 and Nmi and is involved in cytokine signaling. Cell Signal. 19:932–944. 2007. View Article : Google Scholar : PubMed/NCBI
23	Li ZW and Dalton WS: Tumor microenvironment and drug resistance in hematologic malignancies. Blood Rev. 20:333–342. 2006. View Article : Google Scholar : PubMed/NCBI
24	Wang K, Jiang Y, Zheng W, Liu Z, Li H, Lou J, Gu M and Wang X: Silencing of human phosphatidylethanolamine-binding protein 4 enhances rituximab-induced death and chemosensitization in B-cell lymphoma. PLoS One. 8:e568292013. View Article : Google Scholar : PubMed/NCBI
25	Nakagawa Y, Nakayama H, Nagata M, Yoshida R, Kawahara K, Hirosue A, Tanaka T, Yuno A, Matsuoka Y, Kojima T, et al: Overexpression of fibronectin confers cell adhesion-mediated drug resistance (CAM-DR) against 5-FU in oral squamous cell carcinoma cells. Int J Oncol. 44:1376–1384. 2014.PubMed/NCBI
26	Bai H, Li H, Li W, Gui T, Yang J, Cao D and Shen K: The PI3K/AKT/mTOR pathway is a potential predictor of distinct invasive and migratory capacities in human ovarian cancer cell lines. Oncotarget. 6:25520–25532. 2015. View Article : Google Scholar : PubMed/NCBI
27	Liu M, Qi Z, Liu B, Ren Y, Li H, Yang G and Zhang Q: RY-2f, an isoflavone analog, overcomes cisplatin resistance to inhibit ovarian tumorigenesis via targeting the PI3K/AKT/mTOR signaling pathway. Oncotarget. 6:25281–25294. 2015. View Article : Google Scholar : PubMed/NCBI