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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.
AuthorsSabine M Brouxhon, Stephanos Kyrkanides, Veena Raja, Andrew Silberfeld, Xiaofei Teng, Denise Trochesset, Jason Cohen, Li Ma
JournalMolecular cancer therapeutics (Mol Cancer Ther) Vol. 13 Issue 7 Pg. 1791-802 (Jul 2014) ISSN: 1538-8514 [Electronic] United States
PMID24748654 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Copyright©2014 American Association for Cancer Research.
Chemical References
  • Antibodies, Monoclonal
  • Cadherins
  • Tumor Suppressor Protein p53
  • Proto-Oncogene Proteins c-mdm2
  • PTEN Phosphohydrolase
Topics
  • Animals
  • Antibodies, Monoclonal (immunology, pharmacology)
  • Apoptosis (drug effects, immunology)
  • Cadherins (immunology)
  • Carcinoma, Squamous Cell (immunology, metabolism, pathology, therapy)
  • Cell Growth Processes (drug effects, immunology)
  • Down-Regulation
  • Female
  • Humans
  • Mice
  • Mice, SCID
  • Neoplasm Grading
  • PTEN Phosphohydrolase (metabolism)
  • Proto-Oncogene Proteins c-mdm2 (metabolism)
  • Random Allocation
  • Signal Transduction
  • Skin Neoplasms (immunology, metabolism, pathology, therapy)
  • Tumor Suppressor Protein p53 (metabolism)

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