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.