Repression of liver colorectal metastasis by the serpin Spn4A a naturally occurring inhibitor of the constitutive secretory proprotein convertases.

Fatma Sfaxi,Jia Ma,Peter Metrakos,Andreas Bikfalvi,Nathalie Scamuffa,Abdel-Majid Khatib,Hermann Ragg,Géraldine Siegfried,Fabien Calvo,Claude Lalou

doi:10.18632/oncotarget.1966

Abstract

Liver is the most common site of metastasis from colorectal cancers, and liver of patients with liver colorectal metastasis have abnormal levels of the proprotein convertases (PCs). These proteases are involved in the activation and/or expression of various colon cancer-related mediators, making them promising targets in colorectal liver metastasis therapy. Here, we revealed that the serpin Spn4 from Drosophila melanogaster inhibits the activity of all the PCs found in the constitutive secretory pathway and represses the metastatic potential of the colon cancer cells HT-29 and CT-26. In these cells, Spn4A inhibited the processing of the PCs substrates IGF-1R and PDGF-A that associated their reduced anchorage-independent growth, invasiveness and survival in response to apoptotic agents. In vivo, Spn4A-expressing tumor cells showed repressed subcutaneous tumor development and liver metastases formation in response to their intrasplenic inoculation. In these cells Spn4A induced the expression of molecules with anti-metastatic functions and inhibited expression of pro-tumorigenic molecules. Taken together, our findings identify Spn4A as the only endogenous inhibitor of all the constitutive secretory pathway PCs, which is able to repress the metastatic potential of colon cancer cells. These results suggest the potential use of Spn4A and/or derivates as a useful adduct colorectal liver metastasis prevention.

Highlights

By inducing the cleavage and/or expression of various protein precursors, the kexin-like proprotein convertases (PCs) are directly involved in the malignant phenotype of colon cancer cells, and play a key role in colon cancer progression and metastasis [1,2,3,4,5,6,7]
We show that the serpin Spn4A that contains a Furin cleavage motif in its reactive site loop like α1-PDX [23, 24] and reported to inhibit Furin [24] is able to function as an endogenous inhibitor of all the constitutive secretory pathway PCs
In contrast to the regulated secretory pathway convertases PC1 and PC2, to date, there is no naturally occurring inhibitor known that regulates the activity of all PCs found in the constitutive secretory pathway Furin, PACE4, PC5A, PC5B and PC7

Summary

Introduction

By inducing the cleavage and/or expression of various protein precursors, the kexin-like proprotein convertases (PCs) are directly involved in the malignant phenotype of colon cancer cells, and play a key role in colon cancer progression and metastasis [1,2,3,4,5,6,7]. Conversion www.impactjournals.com/oncotarget of PC substrates is mediated by one or more of the seven PC family members. These include PC1 and PC2 found within dense core secretory granules that process proteins secreted by the regulated secretory pathway, and Furin, PC4, PC5, PACE4 and PC7 that are involved in processing of protein precursors secreted via the constitutive secretory pathway [1,2,3,4,5,6,7]. Inhibition of PCs activity by the bioengineered PCs inhibitor α1-PDX [9] or prodomain of Furin [10] in colon carcinoma cell lines resulted in reduced processing of various PC substrates including colon cancer-related proteins [1,2,3,4,5,6,7, 10]

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Results

Conclusion