Inhibition of Endoglin–GIPC Interaction Inhibits Pancreatic Cancer Cell Growth

Abstract

Endoglin, a 180 kDa disulfide-linked homodimeric, transmembrane receptor protein mostly expressed in tumor-associated endothelial cells, is an endogenous binding partner of GAIP-interacting protein, C terminus (GIPC). Endoglin functions as a co-receptor of TβRII that binds Transforming Growth Factor-β (TGF-β) and is important for vascular development, and consequently has become a compelling target for anti-angiogenic therapies. A few recent studies in Gastrointestinal Stromal Tumor (GIST), breast cancer and ovarian cancer, however, suggest that endoglin is upregulated in tumor cells and is associated with poor prognosis. These findings indicate a broader role of endoglin in tumor biology, beyond anti-angiogenic effects. The goal of our current study is to evaluate the effects of targeting endoglin in pancreatic cancer both in vitro and in vivo. We analyzed the anti-proliferative effect of both RNAi-based and peptide ligand-based inhibition of endoglin in pancreatic cancer cell lines, the latter yielding a GIPC PDZ domain-targeting lipopeptide with notable anti-proliferative activity. We further demonstrated that endoglin inhibition induced a differentiation phenotype in the pancreatic cancer cells and sensitized them against conventional chemotherapeutic drug gemcitabine. Most importantly, we have demonstrated the anti-tumor effect of both RNAi based and competitive inhibitor based blocking of endoglin in pancreatic cancer xenograft models in vivo. To our knowledge, this is the first report exploring the effect of targeting endoglin in pancreatic cancer cells.

Endoglin Is Essential for the Maintenance of Self-Renewal and Chemoresistance in Renal Cancer Stem Cells

“…Several studies indicate that CD105 plays a tumor-suppressive role in esophageal squamous cell carcinoma and prostate cancer ( Henry et al., 2011 , Wong et al., 2008 ). However, the preponderance of evidence suggests that CD105 promotes metastasis and chemoresistance ( Dales et al., 2003 , Pal et al., 2014 ). The opposing functional activity of CD105 might be attributed to its different isoforms.…”

Interleukin-6 promotes pancreatic cancer cell migration by rapidly activating the small GTPase CDC42

“…Panc04.03 cells were maintained in RPMI 1640 medium ϩ 10% FBS in the presence of penicillin and streptomycin. Human pancreatic cancer cells 5160-1 and 6741-1, provided by the Mayo Clinic SPORE, were derived from human tumors that were cultured as patient-derived xenografts as described previously (16) and maintained in DMEM/F-12 ϩ 10% FBS in the presence of penicillin and streptomycin. All tissues were obtained and used in accordance with the Mayo Clinic Institutional Review Board and abide by the Declaration of Helsinki principles.…”

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

“…Cell culture. Patient derived cell lines (PDCLs) were generated as previously described 4,[44][45][46] .…”