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Rituximab inhibits the constitutively activated PI3K-Akt pathway in B-NHL cell lines: involvement in chemosensitization to drug-induced apoptosis

A Retraction to this article was published on 27 June 2016


Rituximab (chimeric anti-CD20 monoclonal antibody) is currently being used, alone or in combination with chemotherapy, in the treatment of B-non-Hodgkin's lymphoma (B-NHL). We have reported that rituximab treatment of B-NHL cell lines sensitizes the drug-resistant tumor cells to apoptosis by various chemotherapeutic drugs and chemosensitization was, in large part, owing to the selective inhibition of the anti-apoptotic Bcl-XL gene product. The constitutive activation of the Akt pathway in B-NHL results in overexpression and functional activation of Bcl-xL. Hence, we hypothesized that rituximab-induced inhibition of Bcl-xL expression and chemosensitization may result, in part, from its inhibitory activity of the Akt pathway. This hypothesis was tested using the drug-resistant Ramos and Daudi B-NHL cell lines. Time kinetic analysis revealed that treatment with rituximab inhibited phosphorylation of Akt, but not unphosphorylated Akt, and the inhibition was first detected at 6 h post-rituximab treatment. Similar time kinetics revealed rituximab-induced inhibition of p-PDK1, p-Bad, p-IKKα/β and p-Iκβα and no inhibition of unphosphorylated proteins. In addition, rituximab treatment resulted in significant increase of Bcl-xL–Bad heterodimeric complexes as compared to untreated cells. The role of the Akt pathway in the regulation of resistance was corroborated by the use of the Akt inhibitor, LY294002, and by transfection with siRNA Akt. Treatment of tumor cells with LY294002 or with Akt siRNA, but not control siRNA, resulted in inhibition of Bcl-xL expression and sensitization to drug-induced apoptosis. Although rituximab did not inhibit the Akt pathway nor sensitized the rituximab-resistant Ramos RR1 clone, treatment with LY294002 or Akt siRNA sensitized the clone to drug-induced apoptosis. The present findings demonstrate for the first time that rituximab inhibits the constitutively activated Akt pathway in B-NHL cell lines, and this inhibition contributes to sensitization of drug-resistant cells to apoptosis by chemotherapeutic drugs. The findings also identify the Akt pathway as target for therapeutic intervention in the reversal of rituximab and drug-resistant B-NHL.

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  • Alas S, Bonavida B . (2001). Rituximab inactivates signal transducer and activation of transcription 3 (STAT3) activity in B-non-Hodgkin's lymphoma through inhibition of the interleukin 10 autocrine/paracrine loop and results in down-regulation of Bcl-2 and sensitization to cytotoxic drugs. Cancer Res 61: 5137–5144.

    CAS  PubMed  Google Scholar 

  • Arranz E, Robledo M, Martfnez B, Gallego J, Remain A, Rivas C et al. (1996). Incidence of homogeneously staining regions in non-Hodgkin lymphomas. Cancer Genet Cytogenet 87: 1–3.

    Article  CAS  Google Scholar 

  • Cantley LC . (2002). The phosphoinositide 3-kinase pathway. Science 296: 1655–1657.

    Article  CAS  Google Scholar 

  • Cheng JQ, Ruggeri B, Klein WM, Sonoda G, Altomare DA, Watson DK et al. (1996). Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. Sci USA 93: 3636–3641.

    Article  CAS  Google Scholar 

  • Cheng JQ, Lindsley CW, Cheng GZ, Yang H, Nicosia SV . (2005). The Akt/PKB pathway: molecular target for cancer drug discovery. Oncogene 24: 7482–7492.

    Article  CAS  Google Scholar 

  • Cuni S, Perez-Aciego P, Perez-Chacon G, Vargas JA, Sanchez A, Martin-Saavedra FM et al. (2004). A sustained activation of PI3K/NF-kappaB pathway is critical for the survival of chronic lymphocytic leukemia B cells. Leukemia 18: 1391–1400.

    Article  CAS  Google Scholar 

  • Datta SR, Brunet A, Greenberg ME . (1999). Cellular survival: a play in three Akts. Genes Dev 13: 2905–2927.

    Article  CAS  Google Scholar 

  • Di Cristofano A, Pandolfi PP . (2000). The multiple roles of PTEN in tumor suppression. Cell 100: 387–390.

    Article  CAS  Google Scholar 

  • Ernst JA, Li H, Kim HS, Nakamura GR, Yansura DG, Vandlen RL . (2005). Isolation and Characterization of the B-Cell Marker CD20. Biochemistry 44: 15150–15158.

    Article  CAS  Google Scholar 

  • Goswami A, Ranganathan P, Rangnekar VM . (2006). The phosphoinositide 3-kinase/Akt1/Par-4 axis: a cancer-selective therapeutic target. Cancer Res 66: 2889–2892.

    Article  CAS  Google Scholar 

  • Haiman CA, Stram DO, Cheng I, Giorgi EE, Pooler L, Penney K et al. (2006). Common genetic variation at PTEN and risk of sporadic breast and prostate cancer. Cancer Epidemiol Biomarkers Prev 15: 1021–1025.

    Article  CAS  Google Scholar 

  • Hayakawa J, Ohmichi M, Kurachi H, Kanda Y, Hisamoto K, Nishio Y et al. (2000). Inhibition of BAD phosphorylation either at serine 112 via extracellular signal-regulated protein kinase cascade or at serine 136 via Akt cascade sensitizes human ovarian cancer cells to cisplatin. Cancer Res 60: 5988–5994.

    CAS  PubMed  Google Scholar 

  • Jazirehi AR, Bonavida B . (2005). Cellular and molecular signal transduction pathways modulated by rituximab (rituxan, anti-CD20 mAb) in non-Hodgkin's lymphoma: implications in chemosensitization and therapeutic intervention. Oncogene 24: 2121–2143.

    Article  CAS  Google Scholar 

  • Jazirehi AR, Huerta-Yepez S, Cheng G, Bonavida B . (2005). Rituximab (chimeric anti-CD20 monoclonal antibody) inhibits the constitutive nuclear factor-{kappa}B signaling pathway in non-Hodgkin's lymphoma B-cell lines: role in sensitization to chemo. Cancer Res 65: 264–276.

    CAS  PubMed  Google Scholar 

  • Jazirehi AR, Vega MI, Bonavida B . (2007). Development of rituximab-resistant lymphoma clones with altered cell signaling and cross-resistance to chemotherapy. Cancer Res 67: 1270–1281.

    Article  CAS  Google Scholar 

  • Jazirehi AR, Vega MI, Chatterjee D, Goodglick L, Bonavida B . (2004). Inhibition of the Raf-MEK1/2-ERK1/2 signaling pathway, Bcl-xL down-regulation, and chemosensitization of non-Hodgkin's lymphoma B cells by Rituximab. Cancer Res 64: 7117–7126.

    Article  CAS  Google Scholar 

  • Marsit CJ, Zheng S, Aldape K, Hinds PW, Nelson HH, Wiencke JK et al. (2005). PTEN expression in non-small-cell lung cancer: evaluating its relation to tumor characteristics, allelic loss, and epigenetic alteration. Hum Pathol 36: 768–776.

    Article  CAS  Google Scholar 

  • Osaki M, Oshimura M, Ito H . (2004). PI3K-Akt pathway: its functions and alterations in human cancer. Apoptosis 9: 667–676.

    Article  CAS  Google Scholar 

  • Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB . (1999). NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature 401: 82–85.

    Article  CAS  Google Scholar 

  • Poh TW, Pervaiz S . (2005). LY294002 and LY303511 sensitize tumor cells to drug-induced apoptosis via intracellular hydrogen peroxide production independent of the phosphoinositide 3-kinase-Akt pathway. Cancer Res 65: 6264–6274.

    Article  CAS  Google Scholar 

  • Rennie PS, Nelson CC . (1998). Epigenetic Mechanisms for Progression of Prostate Cancer. Cancer Metastasis Rev 17: 401–409 Review.

    Article  CAS  Google Scholar 

  • Rogers BB . (2006). Overview of non-Hodgkin's lymphoma. Semin Oncol Nurs 22: 67–72.

    Article  Google Scholar 

  • Shan D, Ledbetter JA, Press OW . (1998). Apoptosis of malignant human B cells by ligation of CD20 with monoclonal antibodies. Blood 91: 1644–1652.

    CAS  PubMed  Google Scholar 

  • Sugimori K, Matsui K, Motomura H, Tokoro T, Wang J, Higa S et al. (2005). BMP-2 prevents apoptosis of the N1511 chondrocytic cell line through PI3K/Akt-mediated NF-kappaB activation. J Bone Miner Metab 23: 411–419.

    Article  CAS  Google Scholar 

  • Tachiiri S, Sasai K, Oya N, Hiraoka M . (2000). Enhanced cell killing by overexpression of dominant-negative phosphatidylinositol 3-kinase subunit, Deltap85, following genotoxic stresses. Jpn J Cancer Res 91: 1314–1318.

    Article  CAS  Google Scholar 

  • Toker A, Yoeli-Lerner M . (2006). Akt signaling and cancer: surviving but not moving on. Cancer Res 66: 3963–3966.

    Article  CAS  Google Scholar 

  • Uddin S, Hussain A, Al-Hussein K, Platanias LC, Bhatiaa KG . (2004). Inhibition of phosphatidylinositol 3′-kinase induces preferentially killing of PTEN-null T leukemias through AKT pathway. Biochem Biophys Res Commun 320: 932–938.

    Article  CAS  Google Scholar 

  • Vivanco I, Sawyers CL . (2002). The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2: 489–501.

    Article  CAS  Google Scholar 

  • Weintraub SJ, Manson SR, Deverman BE . (2004). Resistance to antineoplastic therapy. The oncogenic tyrosine kinase-Bcl-x(L) axis. Cancer Cell 5: 3–4.

    Article  CAS  Google Scholar 

  • Wetzker R, Rommel C . (2004). Phosphoinositide 3-kinases as targets for therapeutic intervention. Curr Pharm Des 10: 1915–1922.

    Article  CAS  Google Scholar 

  • Xerri L, Parc P, Brousset P, Schlaifer D, Hassoun J, Reed JC et al. (1996). Predominant expression of the long isoform of Bcl-x (Bcl-xL) in human lymphomas. Br J Haematol 92: 900–906.

    Article  CAS  Google Scholar 

  • Yin D, Woodruff M, Zhang Y, Whaley S, Miao J, Ferslew K et al. (2006). Morphine promotes Jurkat cell apoptosis through pro-apoptotic FADD/P53 and anti-apoptotic PI3K/Akt/NF-kappaB pathways. J Neuroimmunol 174: 101–107.

    Article  CAS  Google Scholar 

  • Zhao WL, Daneshpouy ME, Mounier N, Briere J, Leboeuf C, Plassa LF et al. (2004). Prognostic significance of bcl-xL gene expression and apoptotic cell counts in follicular lymphoma. Blood 103: 695–697.

    Article  CAS  Google Scholar 

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This work was supported in part by a gift from the JCCC Rosenfield Fund under the directorship of David Leveton. We also thank Maggie Yang and Alina Katsman in the preparation of the manuscript.

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Correspondence to B Bonavida.

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Suzuki, E., Umezawa, K. & Bonavida, B. Rituximab inhibits the constitutively activated PI3K-Akt pathway in B-NHL cell lines: involvement in chemosensitization to drug-induced apoptosis. Oncogene 26, 6184–6193 (2007).

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