Wei Zhao1, Jaffer A Ajani2, Guha Sushovan3, Nobuo Ochi3, Rosa Hwang4, Margarete Hafley3, Randy L Johnson5, Robert S Bresalier3, Craig D Logsdon5, Zhiqian Zhang6, Shumei Song7. 1. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education) and Department of Cell Biology, Peking University Cancer Hospital and Institute, Beijing, People's Republic of China; Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas. Electronic address: linelong@126.com. 2. Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas. Electronic address: jajani@mdanderson.org. 3. Department of Gastroenterology, Hepatology, and Nutrition, University of Texas M.D. Anderson Cancer Center, Houston, Texas. 4. Department of Breast Surgical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas. 5. Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston, Texas. 6. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education) and Department of Cell Biology, Peking University Cancer Hospital and Institute, Beijing, People's Republic of China. 7. Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas. Electronic address: ssong@mdanderson.org.
Abstract
BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) is characterized by activated pancreatic stellate cells (PSCs), abundance of extracellular matrix (ECM), and production of cytokines and chemokines. Galectin 3 (GAL3), a β-galactoside-specific lectin, contributes to PDAC development but its effects on the stroma and cytokine production are unclear. METHODS: The effect of recombinant human GAL3 (rGAL3) on activation of PSCs, production of cytokines, and ECM proteins was determined by proliferation, invasion, cytokine array, and quantitative polymerase chain reaction. We assessed co-cultures of PDAC cells with GAL3 genetic alterations with PSCs. Production of interleukin 8 (IL8) and activities of nuclear factor (NF)-κB were determined by enzyme-linked immunosorbent assay and luciferase reporter analyses. We studied the effects of inhibitors of NF-κB and integrin-linked kinase (ILK) on pathways activated by rGAL3. RESULTS: In analyses of the Gene Expression Omnibus database and our dataset, we observed higher levels of GAL3, IL8, and other cytokines in PDAC than in nontumor tissues. Production of IL8, granulocyte-macrophage colony-stimulating factor, chemokine ligand 1, and C-C motif chemokine ligand 2 increased in PSCs exposed to rGAL3 compared with controls. Culture of PSCs with PDAC cells that express different levels of GAL3 resulted in proliferation and invasion of PSCs that increased with level of GAL3. GAL3 stimulated transcription of IL8 through integrin subunit beta 1 (ITGB1) on PSCs, which activates NF-κB through ILK. Inhibitors of ILK or NF-κB or a neutralizing antibody against ITGB1 blocked transcription and production of IL8 from PSCs induced by rGAL3. The GAL3 inhibitor significantly reduced growth and metastases of orthotopic tumors that formed from PDAC and PSC cells co-implanted in mice. CONCLUSION: GAL3 activates PSC cells to produce inflammatory cytokines via ITGB1signaling to ILK and activation of NF-κB. Inhibition of this pathway reduced growth and metastases of pancreatic orthotopic tumors in mice.
BACKGROUND & AIMS:Pancreatic ductal adenocarcinoma (PDAC) is characterized by activated pancreatic stellate cells (PSCs), abundance of extracellular matrix (ECM), and production of cytokines and chemokines. Galectin 3 (GAL3), a β-galactoside-specific lectin, contributes to PDAC development but its effects on the stroma and cytokine production are unclear. METHODS: The effect of recombinant humanGAL3 (rGAL3) on activation of PSCs, production of cytokines, and ECM proteins was determined by proliferation, invasion, cytokine array, and quantitative polymerase chain reaction. We assessed co-cultures of PDAC cells with GAL3 genetic alterations with PSCs. Production of interleukin 8 (IL8) and activities of nuclear factor (NF)-κB were determined by enzyme-linked immunosorbent assay and luciferase reporter analyses. We studied the effects of inhibitors of NF-κB and integrin-linked kinase (ILK) on pathways activated by rGAL3. RESULTS: In analyses of the Gene Expression Omnibus database and our dataset, we observed higher levels of GAL3, IL8, and other cytokines in PDAC than in nontumor tissues. Production of IL8, granulocyte-macrophage colony-stimulating factor, chemokine ligand 1, and C-C motif chemokine ligand 2 increased in PSCs exposed to rGAL3 compared with controls. Culture of PSCs with PDAC cells that express different levels of GAL3 resulted in proliferation and invasion of PSCs that increased with level of GAL3. GAL3 stimulated transcription of IL8 through integrin subunit beta 1 (ITGB1) on PSCs, which activates NF-κB through ILK. Inhibitors of ILK or NF-κB or a neutralizing antibody against ITGB1 blocked transcription and production of IL8 from PSCs induced by rGAL3. The GAL3 inhibitor significantly reduced growth and metastases of orthotopic tumors that formed from PDAC and PSC cells co-implanted in mice. CONCLUSION:GAL3 activates PSC cells to produce inflammatory cytokines via ITGB1signaling to ILK and activation of NF-κB. Inhibition of this pathway reduced growth and metastases of pancreatic orthotopic tumors in mice.
Authors: Peter P Ruvolo; Vivian R Ruvolo; Jared K Burks; YiHua Qiu; Rui-Yu Wang; Elizabeth J Shpall; Leonardo Mirandola; Numsen Hail; Zhihong Zeng; Teresa McQueen; Naval Daver; Sean M Post; Maurizio Chiriva-Internati; Steven M Kornblau; Michael Andreeff Journal: Biochim Biophys Acta Mol Cell Res Date: 2018-04-12 Impact factor: 4.739
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