Oncogenic Ras/ERK Signaling Activates CDCP1 to Promote Tumor Invasion and Metastasis

Abstract

Involvement of Ras in cancer initiation is known, but recent evidence indicates a role in cancer progression, including metastasis and invasion; however, the mechanism is still unknown. In this study, it was determined that human lung cancer cells with Ras mutations, among other popular mutations, showed significantly higher expression of CUB domain-containing protein 1 (CDCP1) than those without. Furthermore, activated Ras clearly induced CDCP1, whereas CDCP1 knockdown or inhibition of CDCP1 phosphorylation by Src-directed therapy abrogated anoikis resistance, migration, and invasion induced by activated-Ras. Activation of MMP2 and secretion of MMP9, in a model of Ras-induced invasion, was found to be regulated through induction of phosphorylated CDCP1. Thus, CDCP1 is required for the functional link between Ras and Src signaling during the multistage development of human malignant tumors, highlighting CDCP1 as a potent target for treatment in the broad spectrum of human cancers associated with these oncogenes.

miR-202 Enhances the Anti-Tumor Effect of Cisplatin on Non-Small Cell Lung Cancer by Targeting the Ras/MAPK Pathway

“…4A, miR-202 decreased KRas expression in cisplatin-treated NCI-H441 and A549 NSCLC cells. Furthermore, we found that the overexpression of miR-202 inhibited the phosphorylation of MEK and ERK because the oncogenic KRas is upstream of the MAPK pathway [7,8]. To emphasize the importance of KRas inhibition in miR-202-promoted cell death in cisplatin-treated NSCLC cells, we performed a KRas loss-of-function assay by transfection with KRas-specific siRNA.…”

“…Ras protein family members are GTPase proteins that initiate the mitogen-activated protein kinase (MAPK) and phosphatydilinositol-3-kinase (PI3K) signaling pathways to regulate cell proliferation, survival, and chemosensitivity [7,8]. In human cells, the Ras family includes the HRas, NRas, and KRas proteins, which are highly homologous.…”

CDCP1 cleavage is necessary for homodimerization-induced migration of triple-negative breast cancer

“…2 Importantly, CDCP1 is involved in metastasis in multiple animal models of cancer, including lung adenocarcinoma, gastric scirrhous carcinoma, melanoma, and prostate and ovarian carcinomas. 3–9 CDCP1 expression is induced by hypoxia in clear-cell renal cell carcinoma (ccRCC) 10,11 and activated Ras in lung cancer, 12 and its localization at the membrane is induced by epidermal growth factor receptor in ovarian cancer. 13 The full-length, 135-kDa CDCP1 protein (flCDCP1) can be cleaved into a 70-kDa, membrane-bound cleaved CDCP1 (cCDCP1) and a 65-kDa portion that is shed on the extracellular side of the membrane.…”

New crossroads for potential therapeutic intervention in cancer - intersections between CDCP1, EGFR family members and downstream signaling pathways

“…CDCP1-mediated pro-cancer effects can also occur via ligand/receptor-independent activation of pathways downstream of cell surface EGFR family members. For example, mutations in the most frequently activated oncogenes, the Ras gene family, activate RAF/MEK/ERK which robustly induce CDCP1 mRNA and protein expression in non-small cell lung cancer (NSCLC) cells [16]. At least in NSCLC cells, p-Y-CDCP1 is required for Ras oncogenic functions including cell migration, invasion, colony formation in soft agar and resistance to anoikis in vitro [16].…”

“…For example, mutations in the most frequently activated oncogenes, the Ras gene family, activate RAF/MEK/ERK which robustly induce CDCP1 mRNA and protein expression in non-small cell lung cancer (NSCLC) cells [16]. At least in NSCLC cells, p-Y-CDCP1 is required for Ras oncogenic functions including cell migration, invasion, colony formation in soft agar and resistance to anoikis in vitro [16]. Signaling via CDCP1, potentially via growth factor receptor axes, can be intensified under hypoxic conditions, a common microenvironment for cancer cells that also contributes to chemoresistance.…”