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Regulation of Vascular Endothelial Growth Factor Receptor-1 Expression by Specificity Proteins 1, 3, and 4In Pancreatic Cancer Cells

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Regulation of Vascular Endothelial Growth Factor Receptor-1 Expression by Specificity Proteins 1, 3, and 4In Pancreatic Cancer Cells Research Article Regulation of Vascular Endothelial Growth Factor Receptor-1 Expression by Specificity Proteins 1, 3, and 4in Pancreatic Cancer Cells Maen Abdelrahim,1,4 Cheryl H. Baker,4 James L. Abbruzzese,2 David Sheikh-Hamad,3 Shengxi Liu,1 Sung Dae Cho,1 Kyungsil Yoon,1 and Stephen Safe1,5 1Institute of Biosciences and Technology, Texas A&M University Health Science Center; 2Department of Gastrointestinal Medical Oncology, University of Texas M. D. Anderson Cancer Center; 3Division of Nephrology, Department of Medicine, Baylor College of Medicine, Houston, Texas; 4Cancer Research Institute, M. D. Anderson Cancer Center, Orlando, Florida; and 5Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas Abstract through their specific interactions with VEGF receptors (VEGFR), Vascular endothelial growth factor receptor-1 (VEGFR1) is which are transmembrane tyrosine kinases and members of the expressed in cancer cell lines and tumors and, in pancreatic PDGF receptor gene family. and colon cancer cells, activation of VEGFR1 is linked to VEGFR1 (Flk-1), VEGFR2(Flt-1/KDR), and VEGFR3 (Flt-4) are the three major receptors for VEGF and related angiogenic factors. increased tumor migration and invasiveness.Tolfenamic acid, The former two receptors are primarily involved in angiogenesis in a nonsteroidal anti-inflammatory drug, decreases Sp protein endothelial cells, whereas VEGFR3 promotes hematopoiesis and expression in Panc-1 and L3.6pl pancreatic cancer cells, and lymphoangiogenesis (2, 3, 7, 8). VEGFR2 plays a critical role in this was accompanied by decreased VEGFR1 protein and angiogenesis; homozygous knockout mice were embryonic lethal mRNA and decreased luciferase activity on cells transfected [gestation day (GD) 8.5–9.0] and this was associated with the with constructs (pVEGFR1) containing VEGFR1 promoter failure to develop blood vessels (9). VEGFA binds with high affinity inserts.Comparable results were obtained in pancreatic to VEGFR2and induces formation of a homodimer, which cancer cells transfected with small inhibitory RNAs for Sp1, subsequently activates downstream signaling pathways similar to Sp3, and Sp4 and all three proteins bound to GC-rich elements other receptor tyrosine kinases. Deletion of the VEGFR1 gene in in the VEGFR1 promoter.These results show that VEGFR1 is mice is also embryolethal at GD of 8.5; however, the embryonic regulated by Sp proteins and that treatment with tolfenamic phenotype is different from that observed in the VEGFR2 acid decreases expression of this critical angiogenic factor. knockouts because embryonic endothelial cells are highly over- Moreover, in vitro studies in Panc-1 cells show that activation grown and disorganized (10, 11). There is evidence that VEGFR1 of VEGFR1 by VEGFB to increase mitogen-activated protein acts, in part, as a decoy receptor that inhibits VEGFR2-mediated kinase 1/2 phosphorylation and cell migration on collagen- angiogenesis (12–14); however, under some conditions, VEGFR1 coated plates is also inhibited by tolfenamic acid.Thus, may also cooperatively activate angiogenesis with VEGFR2and this targeted degradation of Sp proteins is highly effective for response is both ligand and cell context dependent (14). inhibiting VEGFR1 and associated angiogenic responses in VEGFR1 is also expressed as a soluble truncated (sVEGFR1) pancreatic cancer. [Cancer Res 2007;67(7):3286–94] form, which does not contain the intracellular receptor tyrosine kinase domains, and sVEGFR1 acts primarily to bind VEGF and Introduction inhibit angiogenesis (15–18). VEGFR1 is expressed in a variety of Angiogenesis is a process involving new blood vessel formation cancer cell lines and tumors (19–25) and, in colon and pancreatic from existing vessels and is essential for tissue regeneration and cancer cells, activation of VEGFR1 results in epithelial to remodeling during wound healing and for the female reproductive mesenchymal transition, which is linked to increased invasion cycle (1–3). Angiogenesis also plays a role in several diseases, and migration of tumor cells (23–25). For example, VEGFB induced including rheumatoid arthritis, proliferative retinopathy, psoriasis, phosphorylation of mitogen-activated protein kinase (MAPK) and macular degeneration, and cancer, where this pathway is activated enhanced migration in pancreatic cancer cells, and VEGFR1- during tumor progression, growth, and metastasis (1–6). Vascular neutralizing antibody inhibited these responses. permeability factor or vascular endothelial growth factor (VEGF) To develop agents that will modulate VEGFR1 expression, we was initially identified as a key regulator of angiogenesis and is a have investigated the molecular mechanism regulation of VEGFR1 member of the VEGF/platelet-derived growth factor (PDGF) family expression in pancreatic cancer cells. The VEGFR1 promoter of proteins that include VEGF and related splice variants (VEGF121, contains multiple cis elements, including at least three GC-rich VEGF165, VEGF189, and VEGF206) and VEGFB-E placenta growth sites that bind Sp proteins and a proximal early growth response-1 factors 1 and 2(1–3). These growth factors activate angiogenesis (Egr-1) binding sequence (26). Based on results of RNA interference assays and the effects of the nonsteroidal anti-inflammatory drug (NSAID) tolfenamic acid, which decreases Sp protein expression (27), we have now shown that VEGFR1 expression is primarily Requests for reprints: Stephen Safe, Department of Veterinary Physiology and dependent on Sp proteins. Moreover, VEGFB-dependent activation Pharmacology, Texas A&M University, 4466 TAMU, Veterinary Research Building 410, of VEGFR1, which increases MAPK phosphorylation and migration College Station, TX 77843-4466. Phone: 979-845-5988; Fax: 979-862-4929; E-mail: in Panc-1 cells, is also inhibited by tolfenamic acid. Results of this [email protected]. I2007 American Association for Cancer Research. study show that, like VEGF and VEGFR2(27–38), VEGFR1 doi:10.1158/0008-5472.CAN-06-3831 expression is Sp protein dependent, indicating that agents, such Cancer Res 2007; 67: (7). April 1, 2007 3286 www.aacrjournals.org Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2007 American Association for Cancer Research. Sp Proteins Regulate VEGFR1 Expression Figure 1. VEGFR1 expression in pancreatic cancer cells is Sp protein dependent. Transfection with pVEGFR1A (A), pVEGFR1B (B), and pVEGFR1C (C) and small inhibitory RNAs for Sp1 (iSp1), Sp3 (iSp3), or Sp4 (iSp4). Panc-1 cells were transfected with the pVEGFR1 constructs and iSp1, iSp3, or iSp4, and luciferase (LUC) activity was determined as described in Materials and Methods. As a control for the transfection experiment, cells were transfected with a nonspecific small inhibitory RNA (iNS), and luciferase activity for transfection with iNS was set at 100%. All experiments were replicated at least thrice. Columns, mean; bars, SD. *, P < 0.05, significantly decreased luciferase activity. D, effects of iSp1, iSp3, and iSp4 on Sp and VEGFR1 proteins. Panc-1 cells were transfected with iNS, iSp1, iSp3, or iSp4, and whole-cell lysates were analyzed by Western blot analysis as described in Materials and Methods. The experiment was replicated (thrice) and relative expression of individual Sp proteins and VEGFR1 was compared with levels in cells treated with iNS (set at 100%). *, P < 0.05, significantly decreased protein expression. as tolfenamic acid, which decreased expression of these transcrip- purchased from Becton Dickinson Labware (Bedford, MA). Diff-Quik tion factors, are an important class of mechanism-based anti- staining kit was obtained from Dade Behring (Newark, DE). Fetal bovine 32 angiogenic drugs. serum (FBS) was purchased from InterGen (Purchase, NY). [g- P]ATP (300 Ci/mmol) was obtained from Perkin-Elmer Life Sciences. Poly(deox- yinosinic-deoxycytidylic acid) [poly(dI-dC)] and T4 polynucleotide kinase Materials and Methods were purchased from Roche Molecular Biochemicals (Indianapolis, IN). Cell lines, chemicals, biochemical, constructs, and oligonucleo- Antibodies for Sp1, Sp3, Sp4, histone deacetylase (HDAC), h-tubulin, and tides. Panc-1 cells were obtained from the American Type Culture VEGFR1 proteins were obtained from Santa Cruz Biotechnology (Santa Collection (Manassas, VA). L3.6pl cell line was developed at the M. D. Cruz, CA). Extracellular signal-regulated kinase 1/2(ERK1/2)and Anderson Cancer Center (Houston, TX) and kindly provided by Dr. I.J. phosphorylated ERK1/2(pERK1/2)were obtained from Zymed Laborato- Fidler. VEGFR1 promoter luciferase constructs were kindly provided by ries, Inc. (San Francisco, CA). Lysis buffer and luciferase reagent were Dr. Koji Maemura (Department of Cardiovascular Medicine, University of obtained from Promega Corp. (Madison, WI). VEGF promoter constructs Tokyo, Tokyo, Japan). DMEM/F-12with and without phenol red, 100 Â have been described previously (27). antibiotic/antimycotic solution, and lactacystin were purchased from Transfection of pancreatic cancer cells and preparation of nuclear Sigma Chemical Co. (St. Louis, MO). Collagen IV–coated plates were extracts. Cells were cultured in six-well plates in 2mL DMEM/F-12 www.aacrjournals.org 3287 Cancer Res 2007; 67: (7). April 1, 2007 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2007 American Association for Cancer Research. Cancer Research supplemented with 5% FBS. After 16 to 20 h when cells were 50% to 60% peroxidase–conjugated secondary antibody as described
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