title: Ectodomain-specific E-cadherin antibody suppresses skin SCC growth and reduces tumor grade: a multitargeted therapy modulating RTKs and the PTEN-p53-MDM2 axis.
abstract: Tumor cell survival consists of an intricate balance between cell growth and cell death pathways involving receptor tyrosine kinases [RTK; i.e., HER1-4, insulin-like growth factor-1 receptor (IGF-1R), etc.], MDM2, and the tumor suppressor proteins phosphatase and tensin homolog deleted on chromosome ten (PTEN) and p53. We recently demonstrated that shedded E-cadherin extracellular domain fragment (sEcad) is a valid oncogenic target that is significantly increased in human clinical skin squamous cell cancers (SCC) samples, UV-induced mouse tumors, and cells and promotes tumor cell proliferation, migration, and invasion by interacting and activating with the HER-phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) axis. In resected human SCC tumors, we reported enhanced sEcad-HER1, sEcad-HER2, and sEcad-IGF-1R, but not FL-Ecad-RTK interactions. Here, we demonstrate that a sEcad antibody against the ectodomain of E-cadherin suppressed SCC growth and increased tumor differentiation in orthotopic cutaneous SCC xenografts by inhibiting proliferation and inducing apoptosis. A similar anti-sEcad antibody-induced inhibition of proliferation and induction of cell death was evident in PAM212 cells in vitro. Mechanistically, anti-sEcad administration upregulated an array of cell death pathways (i.e., Bad, active caspase-3, and cleaved PARP) and inhibited inhibitors of apoptosis (IAP; survivin, livin, etc.), RTKs (HER1, HER2, p95HER2, and IGF-1R), MAPK and PI3K/mTOR prosurvival signaling. Interestingly, in anti-sEcad mAb-treated tumors and PAM212 cells, this effect was associated with a profound increase in membrane, cytosolic, and nuclear levels of PTEN; enhanced cytosolic p53; and a decrease in MDM2 levels. Overall, our studies suggest that an antibody-based therapy against sEcad may be a novel therapeutic platform for cutaneous SCCs by hampering key proto-oncogenes (RTKs, IAPs, and MDM2) and activating potent tumor suppressor proteins (PTEN and p53) intricately linked to tumor growth and survival.
authors.affiliation: Authors' Affiliations: Departments of Emergency Medicine, Health Sciences Center, Stony Brook University, Stony Brook, New York Sabine.Brouxhon@stonybrook.edu.
authors.forename: Sabine M
authors.initials: SM
authors.lastname: Brouxhon
authors.affiliation: Health Sciences Center, Stony Brook University, Stony Brook, New York.
authors.forename: Stephanos
authors.initials: S
authors.lastname: Kyrkanides
authors.affiliation: Health Sciences Center, Stony Brook University, Stony Brook, New York.
authors.forename: Veena
authors.initials: V
authors.lastname: Raja
authors.affiliation: Health Sciences Center, Stony Brook University, Stony Brook, New York.
authors.forename: Andrew
authors.initials: A
authors.lastname: Silberfeld
authors.affiliation: Health Sciences Center, Stony Brook University, Stony Brook, New York.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Teng
authors.affiliation: Dermatology, and Pathology; and Health Sciences Center, Stony Brook University, Stony Brook, New York.
authors.forename: Denise
authors.initials: D
authors.lastname: Trochesset
authors.affiliation: Dermatology, and Pathology; and.
authors.forename: Jason
authors.initials: J
authors.lastname: Cohen
authors.affiliation: Health Sciences Center, Stony Brook University, Stony Brook, New York.
authors.forename: Li
authors.initials: L
authors.lastname: Ma
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D015820:Cadherins / Q000276:immunology*; D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D048708:Cell Growth Processes / Q000187:drug effects / Q000276:immunology; D015536:Down-Regulation; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D060787:Neoplasm Grading; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D011897:Random Allocation; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D015820:Cadherins; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2; D051059:PTEN Phosphohydrolase