Ras Suppressor-1 (RSU1) in Cancer Cell Metastasis: A Tale of a Tumor Suppressor.

Maria Louca,Vasiliki Gkretsi,Triantafyllos Stylianopoulos

doi:10.3390/ijms21114076

Maria Louca, Vasiliki Gkretsi + Show 1 more

Open Access

https://doi.org/10.3390/ijms21114076

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Abstract

Cancer is a multifactorial disease responsible for millions of deaths worldwide. It has a strong genetic background, as mutations in oncogenes or tumor suppressor genes contribute to the initiation of cancer development. Integrin signaling as well as the signaling pathway of Ras oncogene, have been long implicated both in carcinogenesis and disease progression. Moreover, they have been involved in the promotion of metastasis, which accounts for the majority of cancer-related deaths. Ras Suppressor-1 (RSU1) was identified as a suppressor of Ras-induced transformation and was shown to localize to cell-extracellular matrix adhesions. Recent findings indicate that its expression is elevated in various cancer types, while its role in regulating metastasis-related cellular processes remains largely unknown. Interestingly, there is no in vivo work in the field to date, and thus, all relevant knowledge stems from in vitro studies. In this review, we summarize recent studies using breast, liver and brain cancer cell lines and highlight the role of RSU1 in regulating cancer cell invasion.

Highlights

Cancer is a multifactorial disease with a strong genetic component, as mutations in oncogenes or tumor suppressor genes significantly contribute to the initiation and development of tumors [1,2]
Among all other focal adhesion proteins that connect integrin signaling with intracellular signaling and actin cytoskeleton, Ras Suppressor-1 (RSU1) is of particular interest, as it was originally identified as a suppressor of Ras-dependent oncogenic transformation [43,44]
It was shown that RSU1 was significantly upregulated in increased stiffness conditions, while its silencing diminished the invasive capacity of tumor spheroids through collagen gels. This was mediated by urokinase Plasminogen Activator and Matrix metalloproteinase 13 (MMP13) [70]. Another recent study in breast cancer cells involved transient silencing of RSU1 expression in two breast cancer cell lines and demonstrated that this silencing resulted in downregulation of Growth Differentiation Factor-15 (GDF15), a member of the Transforming Growth Factor-β (TGF-β) family of proteins, known to be associated with actin cytoskeleton reorganization and metastasis [71,72,73]

Summary

Introduction

Cancer is a multifactorial disease with a strong genetic component, as mutations in oncogenes or tumor suppressor genes significantly contribute to the initiation and development of tumors [1,2]. The Formation of ILK-PINCH-PARVA (IPP) Complex at Cell ECM Adhesion Sites Integrin-linked kinase (ILK) is an important component of focal adhesions [19]. It was initially described as an intracellular serine/threonine protein kinase that interacts with the integrin β1 cytoplasmic domain [20] to modulate various cellular functions. PINCH-1 has been found to interact with another focal adhesion protein known as Ras Suppressor 1 (RSU1), and regulate cell survival, migration and spreading [28,32] This interaction was further corroborated by data from a novel two-dimensional (2D)-gel electrophoresis analysis, known as interactions by 2D Gel Electrophoresis Overlap (iGEO) [42]. Affinity purification and mass spectrometry analysis followed which confirmed a core complex consisting of PINCH-1, RSU1, ILK and PARVA

RSU1 in Normal Tissues

Current Clinical Knowledge

Conclusions