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: Moumita Chatterjee, Edgar Ben-Josef, Dafydd G Thomas, Meredith A Morgan, Mark M Zalupski, Gazala Khan, Charles Andrew Robinson, Kent A Griffith, Ching-Shih Chen, Thomas Ludwig, Tanios Bekaii-Saab, Arnab Chakravarti, Terence M Williams
• Journal: Scientific reports (Sci Rep) Vol. 5 Pg. 10867 (Jun 12 2015) ISSN: 2045-2322 [Electronic] England
• PMID: 26065715 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• CAV1 protein, human
• Caveolin 1
• Neoplasm Proteins

Topics

• Animals
• Caveolin 1 (biosynthesis, genetics)
• Cell Line, Tumor
• DNA Repair
• Gene Expression Regulation, Neoplastic
• HEK293 Cells
• Heterografts
• Humans
• Male
• Mice
• Mice, Nude
• Neoplasm Metastasis
• Neoplasm Proteins (genetics, metabolism)
• Neoplasm Transplantation
• Pancreatic Neoplasms (genetics, metabolism, pathology)
• Radiation Tolerance
• Signal Transduction