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.

Phosphatidylserine dictates the assembly and dynamics of caveolae in the plasma membrane

“…Non-caveolar Cav1 has been described to impact a variety of traits necessary for the progression of cancer. In prostate cancer cells, Cav1 influences JAK/STAT and Src signaling with high levels of Cav1 correlating with worse outcomes (58). Importantly, in these cells exposure to radiation or the chemotherapeutic agents, gemcitabine and 5-fluorouracil, results in enhanced levels of Cav1 (58).…”

Prognostic value of metastatic tumoral caveolin-1 expression in patients with resected gastric cancer.

“…Similarly, Cav-1 protein was dysregulated in several other gastrointestinal cancers. Tumoral Cav-1 expression increased in cancers cells compared to their normal counterparts, whereas stromal Cav-1 expression decreased in cancer tissues compared to adjacent normal tissues, such as pancreatic cancer [9,19], esophageal cancer [20], and hepatocellular carcinomas [21]. Cav-1 expression is known to be regulated mainly by inactivation of oncogenes or inactivation of tumor suppressive genes, TGF-β, and oxidative stress in the tumor microenvironment [22,23].…”

“…Previous studies have related Cav-1 overexpression with oncogenic transformation, invasion, and metastasis. Recently, Chatterjee et al have observed that CAV-1 knockdown reduced proliferative, invasive, and migratory properties in multiple pancreatic cancer cell lines [9]. Cav-1 affects several signaling pathways in cellular transformation, including aerobic glycolysis, JAK/STAT, JNK, and Src signaling pathway [9,28].…”

“…Recently, Chatterjee et al have observed that CAV-1 knockdown reduced proliferative, invasive, and migratory properties in multiple pancreatic cancer cell lines [9]. Cav-1 affects several signaling pathways in cellular transformation, including aerobic glycolysis, JAK/STAT, JNK, and Src signaling pathway [9,28]. These conflicting effects may be mediated by the activation status of different domains of Cav-1, which depends on the levels of other molecules in different signaling pathways that are expressed with Cav-1 [11].…”

“…Several studies implicate that Cav-1 is involved in a tumor suppression in vitro and in vivo [7,8]. In contrast, others reported an increased expression of Cav-1 in the more advanced stages of cancers [5,9,10], which still suggest the conflicting impact on cancer progression of Cav-1 protein. These contradictory results could be due to the complex biologic behavior of Cav-1 protein, which depends on the location of this molecule and interaction of signaling pathways [11], which might mean the different roles between primary and metastatic tumors.…”