Elsevier

Drug Discovery Today

Volume 20, Issue 1, January 2015, Pages 156-164
Drug Discovery Today

Review
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Slit/Robo pathway: a promising therapeutic target for cancer

https://doi.org/10.1016/j.drudis.2014.09.008Get rights and content

Highlights

  • Slit and Robo are highly involved in the regulation of physiological processes.

  • The Slit/Robo pathway has a significant role in tumorigenesis and cancer progression.

  • The Slit/Robo pathway is a key regulator of many oncogenic pathways.

  • Molecules targeting the Slit/Robo pathway could be promising anticancer drugs.

Axon guidance molecules, slit glycoprotein (Slit) and Roundabout receptor (Robo), have implications in the regulation of physiological processes. Recent studies indicate that Slit and Robo also have important roles in tumorigenesis, cancer progression and metastasis. The Slit/Robo pathway can be considered a master regulator for multiple oncogenic signaling pathways. Herein, we provide a comprehensive review on the role of these molecules and their associated signaling pathways in cancer progression and metastasis. Overall, the current available data suggest that the Slit/Robo pathway could be a promising target for development of anticancer drugs.

Introduction

The development of the nervous system involves several progressive and regressive events that are mainly driven by axon guidance molecules [1], such as Slit and Roundabout (Robo) [2]. Slit/Robo signaling was first established as an extracellular signature to guide axon path finding, promote axon branching and control neuronal migration. The interaction of Slit and Robo proteins is crucially involved in the developmental processes of various vital organs such as breast, lung, liver, kidney, eye and reproductive systems. Slit proteins are highly conserved, secreted glycoproteins that mediate their functions by binding to the transmembrane receptors known as Robo recptors [1]. Slits and Robos are large proteins involved in several cell signaling pathways including axon guidance, cell proliferation, cell motility and angiogenesis 2, 3, 4. Slit and Robo proteins were first discovered as secreted proteins in Drosophila 5, 6, 7. Thereafter, homologs of Slit and Robo proteins have been discovered in rat, mice and humans [8]. Many reports have suggested that, in addition to axon guidance, the Slit/Robo pathway is also involved in the developmental processes and in the regulation of several physiological processes. An aberrant Slit/Robo expression in cells can lead to cancer development, progression and metastasis. Herein, we have reviewed recent advances regarding the roles of the Slit/Robo pathway and proteins in different types of cancer, molecular crosstalk and the modulation of oncogenic signaling pathways.

Section snippets

Structure of Slit and Robo proteins

In humans, Slits are composed of a single peptide of about 1500 amino acids, and there are three members: Slit1, Slit2 and Slit3 9, 10. The primary structure of Slit contains four domains at the N terminus (D1–D4) with leucine-rich repeats (LRR), six EGF-like sequences (EGF), a laminin-G domain and a C terminus with a cysteine-rich knot (Fig. 1) 9, 11, 12. All vertebrates have similar Slit family protein structures. The D2 region domain of LRR of Slits is highly conserved and plays an important

Slit/Robo pathway in cancer progression

The first link between Slit/Robo signaling and cancer was reported by Sundaresan et al. [14]. Subsequent studies indicated that the exon 2 of Robo1 was deleted in lung and breast tumor cell lines 14, 15. Subsequently, various studies have shown that Slit1–3 and Robo 1,3 promoters are hypermethylated (epigenetic inactivation) in several different types of cancers 9, 16, 17, 18, 19, 20. The activation or suppression of the Slit/Robo pathway modulates several oncogenic signaling pathways that are

Role of Slit/Robo pathway in different cancers

The tumor suppressor or antitumor activity of the Slit/Robo pathway is not unanimous, and how cancer-specific expression of Slit and Robo proteins govern the different type of cancers is not clearly comprehended. This section summarizes the recent updates on the regulation of oncogenesis by the Slit/Robo pathway in different cancer types.

Future prospects for Slit/Robo pathway as a drug target

Besides functioning as axon guidance molecules, the Slit/Robo pathway proteins also regulate functions such as morphogenesis of tissue as well as performing many non-neuronal roles such as cell growth, migration and cell survival [92]. Slit/Robo is often downregulated in the advanced stage of most tumors 36, 85, 86. In vitro studies suggested that expression of Slit can be regulated by stress and optimum function can be achieved by modulating the endoplasmic reticulum (ER), Ca2+ homeostasis and

Concluding remarks

The overall data suggest that the axon guidance molecule Slit/Robo has important roles in cancer metastasis, tumorigenesis in many tumors and that several possible tumor-specific expressions need to be explored in future studies. However, additional research is necessary before we can provide a robust, comprehensive mechanism to target the Slit/Robo pathway in the specific cancers. Tumor-specific discrepancy of Slit/Robo by previous authors might simply tempt one to apply neurobiological models

Conflict of interest

The authors have no conflict of interest to declare regarding this work.

Acknowledgements

The authors thank Cathy Christopherson (Sanford Research) for editorial assistance. This work was partially supported by grants from: the National Institutes of Health (R01 CA142736 to S.C.C. and U01 CA162106A to S.C.C. and M.J.); Department of Defense (PC073887 to S.C.C. and PC073643 to M.J.); and the College of Pharmacy (2013 Dean's Seed Grant of the University of Tennessee Health Science Center to M.J. and M.M.Y.).

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