Abstract 4435: Overexpression of Rhotekin confers gastric cancer cells resistance to interferon-α-mediated growth inhibition

Abstract

Tumor infiltrating lymphocytes (TILs) are frequently detected in a variety of malignancies, including gastric cancer (GC). TILs are known to produce high level of interferon-gamma (IFN-γ) in GC, but fail to suppress tumor growth. We have previously shown that Rhotekin (RTKN), the gene encoding the Rho effector RTKN, is overexpressed in human GC, and its expression is correlated with disease progression. In this study, we show that RTKN expression efficiently blocks IFN-γ-mediated anti-growth and immunologic responses, suggesting a role of RTKN in attenuating tumor immunosurveillance during GC pathogenesis. We show that RTKN attenuates STAT1 phosphorylation in response to IFN-γ, and confers increased resistance to IFN-γ-mediated growth suppression in GC cells through inhibiting the expression of STAT1-dependent downstream target genes, including cyclin-dependent kinase inhibitor p21 and antiapoptotic genes BCL-2 and BCL-xL. Conversely, elimination of RTKN expression by knockdown approach facilitates IFN-γ-mediated STAT1 phosphorylation and promotes IFN-γ-mediated growth arrest and apoptosis. We further show that RTKN-mediated inhibition of STAT1 phosphorylation can be reversed by the treatment of sodium orthovanadate, a tyrosine phosphatase inhibitor, suggesting the involvement of tyrosine phosphatases in RTKN-mediated process. In support, our data show that RTKN suppresses IFN-γ-mediated STAT1 phosphorylation partly through facilitating the interactions of SHP2 and STAT1. In summary, our data suggest that RTKN overexpression confers growth advantages to GC by evading immunosurveillance through suppression of IFN-γ-mediated anti-tumor activity. 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 4435. doi:1538-7445.AM2012-4435

Silencing of RTKN2 by siRNA suppresses proliferation, and induces G1 arrest and apoptosis in human bladder cancer cells

“…RTKN belongs to the group of proteins containing a Rho-binding domain, which are target peptides (effectors) for Rho-GTPases (14). A previous study identified a novel cDNA exhibiting homology with human RTKN, designated RTKN2, and was observed in the cytosol and nucleus of CHO cells (4).…”

RTKN2 is Associated with Unfavorable Prognosis and Promotes Progression in Non-Small-Cell Lung Cancer

“… 8 RTKNs are Rho effector proteins, and are expressed in lymphocytes and bone marrow-derived cells, 9 , 16 as well as in lung, colon, thymus, and brain. 17 Two RTKN proteins, RTKN1 and RTKN2, with the same Rho GTPase binding domain, have homologues in mammals. 18 RTKN2 may play a critical role in cell proliferation, apoptosis, and metastasis in many malignant tumor cells.…”

Rhotekin 2 silencing inhibits proliferation and induces apoptosis in human osteosarcoma cells

“…Therefore, it is important to identify additional potential treatments. RTKN are members of a Rho effector protein [ 15 ]. The involvement of RTKN2 in several types of cancer has been reported [ 16–18 ].…”