• 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • br Acknowledgements The authors thank Drs C Klein I


    Acknowledgements The authors thank Drs. C. Klein, I. Canisso and A. Claes with assistance in obtaining tissues. Supported by the Albert G. Clay Endowment, University of Kentucky.
    Introduction Neoplastic cells often develop drug resistance during tumor progression or cancer treatment (Turner and Reis-Filho, 2012). Several molecular mechanisms can lead to drug resistance, one of which being the modulation of the NF-κB pathway (Turco et al., 2004). The NF-κB family of transcriptional factors can be activated by various stimuli. Upon activation, NF-κB dissociates from the inhibitory IκBα and translocates from the cytoplasm to the nucleus, where it binds to the promoter elements and activates gene expression (Ghosh et al., 1998). The increased activity of NF-κB has been shown in a variety of cancer cell types where its activation contributes to aggressive tumor growth as well as to resistance to chemotherapy or ionizing radiation during cancer treatment. The induction of chemo- and radio-resistance is mediated through numerous NF-κB-regulated genes. This involves overexpression of its downstream targets, such as Bcl-xL, Bcl–2, IAP1, and IAP2, and proliferative genes such as cyclin D1 and COX-2. Components of the NF-κB pathway therefore represent key therapeutic targets (Braun et al., 2006, Orlowski and Baldwin, 2002). Hence, inhibition of the NF-κB pathway leads to apoptosis induced through the collapse of the mitochondrial membrane and the activation of caspase-9. Activation of the mitochondrial apoptotic pathway secondary to the inhibition of NF-κB is a valuable source of cell death induction in cancer cells where the expression of NF-κB is elevated (Karin, 2006, Kim et al., 2006). It has been demonstrated that cancer cells transiently pretreated with a sublethal concentration of doxorubicin became more resistant to doxorubicin upon subsequent challenges. Pretreatment of the cells with common biologic modulators, such as tamoxifen, dexamethasone, and curcumin, overcame the doxorubicin-induced NF-κB activation, indicating that this inhibition may play an important role in sensitizing cancer cells to chemotherapeutic drugs (Chuang et al., 2002). In the course of our previous research, the EP4 receptor has been identified as conveying the growth-inhibitory effects of PGE2 in immature and mature Picrotoxin (Murn et al., 2008, Prijatelj et al., 2011). The EP4 receptor is one of the four prostaglandin E (EP) receptors (EP1, EP2, EP3 and EP4) that recognize prostaglandin E2 (PGE2) as its natural binding ligand. Depending on the cell type, activation of the EP4 receptor by PGE2 leads to elevated levels of cAMP and, in some cases, to the activation of cAMP-independent pathways including modulation of the NF-κB transcription factor (Prijatelj et al., 2012). We have, therefore, hypothesized that the EP4 receptor presents a potent therapeutic target for B leukemia and lymphoma treatment. In the present study, we identified a subset of B leukemia and lymphoma cells responding to the growth-inhibitory effects of the selective EP4 receptor agonist, 1-hydroxy prostaglandin E1 (Pge1-OH). Moreover, activation of EP4 receptor by Pge1-OH leads to a decrease in the NF-κB-mediated expression of the antiapoptotic gene Bcl-xL, resulting in an increased sensitivity of cells towards bortezomib- and doxorubicin-induced chemotherapeutic effects.
    Materials and methods
    Discussion In this study, we demonstrated that activation of the EP4 receptor is selectively cytotoxic for malignantly transformed B cells. The effects of the selective EP4 agonist, Pge1-OH, involved inhibition of the NF-κB pathway as well as chemo-sensitization to doxorubicin- and bortezomib- induced cell death. Several approaches have been pursued for the specific modulation of defined cellular death pathways in order to find novel apoptosis-inducing cell-specific targets, so as to increase the efficacy of chemotherapy and to reduce chemotherapy-mediated side effects. Recently, the EP4 receptor has been recognized as the main receptor conveying PGE2-mediated inhibitory effects in mature and immature B cells and could, therefore, represent a potential therapeutic target in various B leukemia and lymphoma malignancies. In order to test this hypothesis, we have evaluated the pharmacological effects of the selective EP4 receptor agonist Pge1-OH on various B (Ramos, MHH-PRE B, NALM-6, KOPN-8), T (MOLT-4, Jurkat) and myeloid (THP-1, U937) leukemia and lymphoma cell lines. These cells express detectable levels of the EP4 receptor; however, B leukemia and lymphoma cells responded to the Pge1-OH treatment with decreased cell proliferation. The selectively toxic effect of Pge1-OH towards malignant B cells was further delineated with the use of lymphoblastoid cells (LCLs). LCLs were generated with Epstein–Barr virus (EBV) transformation of freshly isolated B lymphocytes obtained from blood of healthy donors. The cells retain most of phenotypic properties of B lymphocytes, including the expression of surface markers CD19, CD20 and production of antibodies. They are therefore considered as a valuable model of primary B lymphocytes (Abbasi et al., 2012, Morag et al., 2010). LCLs were assayed under the same conditions as other cell types. As shown in Fig. 1A and B, Pge1-OH had no effect on the viability of LCLs. This selective toxicity indicates the potential of EP4 as a prominent target for treatment of B leukemias and lymphomas. The observed effects underscore previous observations that EP4 receptor activation leads to cell-specific phenotypic responses (Harris, 2002).