TY - JOUR
T1 - Caveolin-1 is associated with tumor progression and confers a multi-modality resistance phenotype in pancreatic cancer
AU - Chatterjee, Moumita
AU - Ben-Josef, Edgar
AU - Thomas, Dafydd G.
AU - Morgan, Meredith A.
AU - Zalupski, Mark M.
AU - Khan, Gazala
AU - Andrew Robinson, Charles
AU - Griffith, Kent A.
AU - Chen, Ching Shih
AU - Ludwig, Thomas
AU - Bekaii-Saab, Tanios
AU - Chakravarti, Arnab
AU - Williams, Terence M.
N1 - Funding Information:
The authors would like to thank Adriana Estrada for assistance with technical aspects of some of the experiments. This work was supported by the following grants: Conquer Cancer Foundation YIA (TW), American Cancer Society Institutional Research Grant IRG-67-003-47 (TW), and Award Number Grant KL2TR001068 from the National Center for Advancing Translational Sciences (TW). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Advancing Translational Sciences or the National Institutes of Health. Additional support was provided by the Pancreatic Cancer Cure Fund (T.B-S.).
PY - 2015/6/12
Y1 - 2015/6/12
N2 - 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.
AB - 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.
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U2 - 10.1038/srep10867
DO - 10.1038/srep10867
M3 - Article
C2 - 26065715
AN - SCOPUS:84935834080
SN - 2045-2322
VL - 5
JO - Scientific reports
JF - Scientific reports
M1 - 10867
ER -