Abstract 2154: CDCP1 links RAS and Src signaling pathways as a common effector for the promotion of tumor metastasis

Abstract

Abstract The oncogenic RAS is one of the most intensively studied proteins which are well recognized as a master regulator of cancer initiation and progression, however rather limited information is available as for their contribution to the cell properties associated with tumor metastasis such as anoikis resistance, cell migration and invasion. We have revealed that CUB domain-containing protein 1 (CDCP1) protein, a substrate of Src family kinase (SFK), in solid cancers is involved in the regulation of anoikis resistance, cell migration and invasion. CDCP1 contributes significantly to the metastatic potential of various cancers including lung, stomach, and pancreatic cancers in a tyrosine phosphorylation dependent manner. It was recently observed that human lung cancer cell lines with K-RAS mutations show significantly higher expression of CDCP1 than those without, while the other common mutations such as EGFR, LKB1 and p53 did not show such relationship. The introduction of the activating mutation of K-RAS clearly induced the expression of CDCP1 and that this enhancement is also affected by the expression levels of Myc protein. Treatment of PD98059, an inhibitor of MEK downstream of Ras, as well as expression of dominant-negative Ras, reduced the expression of CDCP1, and at the same time suppressed cell survival in suspension culture, cell migration and invasion. However, these properties were rescued only when both CDCP1 and Fyn, a member of SFKs were expressed. On the contrary, metastatic potentials caused by expression of activated K-Ras in lung cancer cells was blocked by knockdown of in CDCP1 expression induced by Ras. Using three dimensional organotypic culture assay of human cervical keratinocytes (HCKs) which mimics in vivo tissue invasion of cervical cancers, marked expression of CDCP1 was detected at the site of cell invasion into the collagen raft. The treatment of CDCP1 siRNA or SFKs inhibitor PP2 repressed cell invasion into the collagen raft induced by Ras and Myc. As a summary, it was revealed that expression of CDCP1 is induced by oncogenic Ras, and upregulated CDCP1 triggers cancer invasion and metastasis when phosphorylated by SFKs. Metastatic potential induced by Ras is dependent on the CDCP1 induction, while CDCP1 is not responsive for proliferative change also induced by Ras. These findings demonstrated the central role of CDCP1 as the functional link between RAS and SFKs signaling during the progression of human malignant tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2154. doi:1538-7445.AM2012-2154