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Nuclear Factor-KB Contributes to Hedgehog Signaling Pathway Activation Through Sonic Hedgehog Induction in Pancreatic Cancer

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Nuclear Factor-KB Contributes to Hedgehog Signaling Pathway Activation Through Sonic Hedgehog Induction in Pancreatic Cancer Research Article Nuclear Factor-KB Contributes to Hedgehog Signaling Pathway Activation through Sonic Hedgehog Induction in Pancreatic Cancer Hiroshi Nakashima,1 Masafumi Nakamura,1 Hiroshi Yamaguchi,2 Naoki Yamanaka,1 Takashi Akiyoshi,1 Kenichiro Koga,1 Koji Yamaguchi,3 Masazumi Tsuneyoshi,2 Masao Tanaka,3 and Mitsuo Katano1 Departments of 1Cancer Therapy and Research, 2Anatomic Pathology, and 3Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan Abstract The hedgehog (Hh) signaling pathway is crucial to growth and The hedgehog (Hh) signaling pathway, which functions as an patterning in a wide variety of tissues during embryonic organizer in embryonic development, is implicated in the development (3, 4). Of three Hh ligands, sonic Hh (Shh), Indian development of various tumors. In pancreatic cancer, pathway Hh (Ihh), and desert Hh (Dhh), Shh is reported to play an essential activation is reported to result from aberrant expression of role in the development of pancreatic cancer as well as pancreatic organogenesis (5, 6). Shh undergoes extensive post-translational the ligand, sonic Hh (Shh). However, the details of the mechanisms regulating Shh expression are not yet known. modifications to become biologically active (7). The signal peptide We hypothesized that nuclear factor-KB (NF-KB), a hallmark is cleaved from the precursor form of Shh to yield the 45-kDa transcription factor in inflammatory responses, contributes to full-length form. Further processing of this molecular form of Shh the overexpression of Shh in pancreatic cancer. In the present generates a 19-kDa amino and 26-kDa COOH-terminal peptides. study, we found a close positive correlation between NF-KB The 19-kDa NH2-terminal peptide undergoes COOH-terminal p65 and Shh expression in surgically resected pancreas esterification to a cholesterol molecule before being secreted into specimens, including specimens of chronic pancreatitis and the extracellular spaces where it mediates the physiologic actions pancreatic adenocarcinoma. We showed that blockade of of Shh (8). The response to Shh is mediated by two transmembrane NF-KB suppressed constitutive expression of Shh mRNA in proteins, Smoothened (Smo) and Patched (Ptc), and by down- stream transcription factors that are members of the Gli family. In pancreatic cancer cells. Further activation of NF-KBby inflammatory stimuli, including interleukin-1B, tumor necro- the absence of Shh, Ptc suppresses the signaling activity of Smo. sis factor-A, and lipopolysaccharide, induced overexpression When Shh binds Ptc, Ptc is inactivated, enabling signaling via Smo. of Shh, resulting in activation of the Hh pathway. Over- Smo releases the transcription factor Gli from a large protein expression of Shh induced by these stimuli was also sup- complex, and Gli translocates to the nucleus to activate Hh target pressed by blockade of NF-KB. NF-KB-induced Shh expression genes, including Ptc1 (3, 4). It has been reported that the plant- actually activated the Hh pathway in a ligand-dependent derived teratogenic steroidal alkaloid cyclopamine inhibits the Hh manner and enhanced cell proliferation in pancreatic cancer pathway by antagonizing Smo (9). cells. In addition, inhibition of the Hh pathway as well as Recently, ligand-dependent activation of the Hh pathway, NF-KB suppressed the enhanced cell proliferation. Our data especially due to aberrant expression of its ligand, Shh, has been suggest that NF-KB activation is one of the mechanisms detected in pancreatic cancer, and cyclopamine suppresses the underlying Shh overexpression in pancreatic cancer and that growth of pancreatic cancer cells both in vitro and in vivo (10). proliferation of pancreatic cancer cells is accelerated by These findings suggest that the Hh pathway may be a viable therapeutic target for treatment of pancreatic cancer, but it NF-KB activation in part through Shh overexpression. (Cancer Res 2006; 66(14): 7041-9) remains unclear how Shh is regulated in pancreatic cancer (11). One clue toward identification of the factors regulating Shh is the similarity between cancer development and tissue repair, a late Introduction phase of inflammation. It has been reported that, during repair of Pancreatic cancer is one of the most lethal of all malignancies. bronchial epithelium, transient activation of the Hh pathway Therapeutic options for patients with unresectable, metastatic, or occurs within the normally quiescent bronchial epithelium, and recurrent disease are extremely limited, and few patients survive such a process may well occur during adult gut epithelial turnover for 5 years, which underscores the need for new therapies (1, 2). A (12, 13). better understanding of the mechanisms that underlie develop- Association between chronic inflammation and the development ment of pancreatic cancer would help to identify novel molecular of cancer has been recognized for several years (14–18). Various targets for treatment. cytokines, such as tumor necrosis factor-a (TNF-a) and interleu- kin-1 (IL-1), which seem to play roles in inflammatory responses and the fibrotic reaction, are overexpressed in pancreatic cancer Requests for reprints: Mitsuo Katano, Department of Cancer Therapy and (19–21). Most of these cytokines are potent activators of nuclear Research, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, factor-nB (NF-nB), which has been reported to be also activated in Higashi-ku, Fukuoka 812-8582, Japan. Phone: 81-92-642-6941; Fax: 81-92-642-6221; pancreatic cancer (22, 23). NF-nB is a transcription factor that E-mail: [email protected]. I2006 American Association for Cancer Research. controls expression of numerous genes involved in inflammation doi:10.1158/0008-5472.CAN-05-4588 and immune response processes, including proliferation, invasion www.aacrjournals.org 7041 Cancer Res 2006; 66: (14). July 15, 2006 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 2006 American Association for Cancer Research. Cancer Research and adhesion, angiogenesis, and apoptosis (22). In most unstimu- Science (Sapporo, Japan). Cells were transfected with 0.5 Amol/L NF-nB lated, normal cells, NF-nB is present in the cytoplasm as an inactive decoy or scramble oligodeoxynucleotides with LipofectAMINE (Life heterodimer composed of the p50, p65, and InBa subunits. After Technologies, Inc., Gaithersburg, MD) according to the manufacturer’s activation, InBa undergoes phosphorylation and ubiquitination- instructions. Transfected cells were used for experiments 48 hours after transfection. pIRES2-hSHH-EGFP (referred to as pSHH-GFP) and dependent degradation by the proteasome. Consequently, nuclear pcDNA3.1/His-hGli1 (referred to as pGli1) were kindly provided by Dr. localization signals on the p50-p65 heterodimer are exposed, Aubie Shaw (Division of Urology, Department of Surgery, University of leading to nuclear translocation and binding to a specific Wisconsin, Madison, WI; ref. 27) and Dr. H. Sasaki (Center for consensus sequence that activates gene transcription, including Developmental Biology, RIKEN, Kobe, Japan; ref. 28), respectively. pCMV- genes encoding inflammatory cytokines, chemokines, growth InBa wild-type (WT) and pCMV-InBa mutant were purchased from BD factors, cell adhesion molecules, and cytokine receptors (24). Biosciences/Clontech (Palo Alto, CA). Cells seeded in six-well plates were In the present study, we hypothesized that NF-nB activation up- transfected with 2 Ag plasmid with TransFast reagent (Promega, Madison, regulates expression of Shh, resulting in activation of Hh signaling WI) per manufacturer’s protocol. Cells were used for experiments 48 hours in pancreatic cancer. We first investigated the expression of both after transfection. To collect control medium and Shh-rich medium, Cos7 A NF-nB and Shh in clinical samples of pancreas. We then examined cells were transfected with 2 g pGFP and pSHH-GFP, respectively, with the effect of NF-nB activity on Shh expression and Hh pathway Superfect reagent (Qiagen, Valencia, CA) according to the manufacturer’s instructions. Supernatant was collected 48 hours later and dissolved in activation in pancreatic cancer cells. Finally, we explored the n complete culture medium at a 1:10 dilution. The supernatant from cells biological significance of the correlation between NF- B and transfected with pSHH-GFP was called Shh-rich medium, whereas activation of the Hh pathway in proliferation of pancreatic cancer supernatants from cells transfected with pGFP were collected as control cells. medium. Luciferase assay. Cells in six-well plates were transfected with plasmids with Superfect transfection reagent according to the manufacturer’s Materials and Methods instructions. Cells on each well were cotransfected with 5 ng pRL- Cell culture, reagents, and antibodies. Two human pancreatic ductal SV40 (Promega) and 2 Ag pELAM-Luc (29), the NF-nB-dependent adenocarcinoma (PDAC) cell lines (AsPC-1 and SUIT-2; ref. 25) and Cos7, an luciferase reporter (kindly provided by Dr. K. Takeda, Division of SV40-immortalized monkey kidney cell line, were maintained in RPMI 1640 Embryonic and Genetic Engineering, Medical Institute of Bioregulation, (Life Technologies, Grand Island, NY) supplemented with 10% FCS (Life Kyushu University). After 24 hours of pretreatment with PDTC or Technologies) and antibiotics [100 units/mL penicillin (Meijiseika, Tokyo, cyclopamine, IL-1h or TNF-a was added to each well, and luciferase Japan) and 100 Ag/mL streptomycin
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