title: Caveolin-1 is Associated with Tumor Progression and Confers a Multi-Modality Resistance Phenotype in Pancreatic Cancer.
abstract: Caveolin-1 (Cav-1) is a 21 kDa protein enriched in caveolae, and has been implicated in oncogenic cell transformation, tumorigenesis, and metastasis. We explored roles for Cav-1 in pancreatic cancer (PC) prognostication, tumor progression, resistance to therapy, and whether targeted downregulation could lead to therapeutic sensitization. Cav-1 expression was assessed in cell lines, mouse models, and patient samples, and knocked down in order to compare changes in proliferation, invasion, migration, response to chemotherapy and radiation, and tumor growth. We found Cav-1 is overexpressed in human PC cell lines, mouse models, and human pancreatic tumors, and is associated with worse tumor grade and clinical outcomes. In PC cell lines, disruption/depletion of caveolae/Cav-1 reduces proliferation, colony formation, and invasion. Radiation and chemotherapy up-regulate Cav-1 expression, while Cav-1 depletion induces both chemosensitization and radiosensitization through altered apoptotic and DNA repair signaling. In vivo, Cav-1 depletion significantly attenuates tumor initiation and growth. Finally, Cav-1 depletion leads to altered JAK/STAT, JNK, and Src signaling in PC cells. Together, higher Cav-1 expression is correlated with worse outcomes, is essential for tumor growth and invasion (both in vitro and in vivo), is responsible for promoting resistance to therapies, and may serve as a prognostic/predictive biomarker and target in PC.
authors.affiliation: The Ohio State University Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, OH 43210.
authors.forename: Moumita
authors.initials: M
authors.lastname: Chatterjee
authors.affiliation: Hospital of the University of Pennsylvania, Philadelphia, PA, 19104.
authors.forename: Edgar
authors.initials: E
authors.lastname: Ben-Josef
authors.affiliation: University of Michigan Medical Center, Ann Arbor, MI, 48109.
authors.forename: Dafydd G
authors.initials: DG
authors.lastname: Thomas
authors.affiliation: University of Michigan Medical Center, Ann Arbor, MI, 48109.
authors.forename: Meredith A
authors.initials: MA
authors.lastname: Morgan
authors.affiliation: University of Michigan Medical Center, Ann Arbor, MI, 48109.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Zalupski
authors.affiliation: Henry Ford Hospital System, West Bloomfield, MI, 48322.
authors.forename: Gazala
authors.initials: G
authors.lastname: Khan
authors.affiliation: The Ohio State University Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, OH 43210.
authors.forename: Charles
authors.initials: C
authors.lastname: Andrew Robinson
authors.affiliation: University of Michigan Medical Center, Ann Arbor, MI, 48109.
authors.forename: Kent A
authors.initials: KA
authors.lastname: Griffith
authors.affiliation: The Ohio State University Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, OH 43210.
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
authors.affiliation: The Ohio State University Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, OH 43210.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ludwig
authors.affiliation: The Ohio State University Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, OH 43210.
authors.forename: Tanios
authors.initials: T
authors.lastname: Bekaii-Saab
authors.affiliation: The Ohio State University Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, OH 43210.
authors.forename: Arnab
authors.initials: A
authors.lastname: Chakravarti
authors.affiliation: The Ohio State University Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, OH 43210.
authors.forename: Terence M
authors.initials: TM
authors.lastname: Williams
mesh_terms: D000818:Animals; D051242:Caveolin 1 / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D004260:DNA Repair; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011836:Radiation Tolerance; D015398:Signal Transduction
chemical_list: C495540:CAV1 protein, human; D051242:Caveolin 1; D009363:Neoplasm Proteins