Hepatocyte SLAMF3 reduced specifically the multidrugs resistance protein MRP-1 and increases HCC cells sensitization to anti-cancer drugs.

Grégory Fouquet,Mickael Naassila,Hakim Ouled-Haddou,Véronique Debuysscher,Eric Nguyen-Khac,Jean-Marc Regimbeau,Baptiste Demey,Christèle Ossart,Hicham Bouhlal,Mélanie Simoes Eugenio,Mohammed Al Bagami,Ingrid Marcq,Amrathlal Rabbind Singh

doi:10.18632/oncotarget.8679

Abstract

Multidrug resistance MDR proteins (MRPs) are members of the C family of a group of proteins named ATP binding cassette (ABC) transporters. MRPs can transport drugs including anticancer drugs, nucleoside analogs, antimetabolites and tyrosine kinase inhibitors. Drugs used in HCC therapy, such as tyrosine kinase inhibitor sorafenib, are substrates of uptake and/or efflux transporters. Variable expression of MRPs at the plasma membrane of tumor cells may contribute to drug resistance and subsequent clinical response. Recently, we reported that the hepatocyte SLAMF3 expression (Signaling Lymphocytic Activation Molecule Family member 3) was reduced in tumor cells from hepatocellular carcinoma (HCC) compared to its high expression in adjacent tissues. In the present study, we make a strong correlation between induced SLAMF3 overexpression and the specific loss of MRP-1 expression and its functionalities as a drugs resistance transporter. No changes were observed on expression of ABCG2 and MDR. More importantly, we highlight a strong inverse correlation between MRP-1 and SLAMF3 expression in patients with HCC. We propose that the SLAMF3 overexpression in cancerous cells could represent a potential therapeutic strategy to improve the drugs sensibility of resistant cells and thus control the therapeutic failure in HCC patients.

Highlights

Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide
Transcripts from human hepatocellular carcinoma (HCC) cell line Huh-7 cells were extracted and multidrug resistance (MDR), ABCG2 and MDR proteins (MRPs)-1 genes expression was quantified by Q-PCR
We show that MDR, ABCG2 and MRP were highly expressed by Huh-7 cells (Figure 1a, 1b, 1c)

Summary

Introduction

Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide. Regardless of the etiology, only patients with HCC at an early stage can benefit www.impactjournals.com/oncotarget from therapies such as radical surgical resection, liver transplantation, or the local percutaneous ablation. Therapy based on anti-multikinases such as, Sorafenib, is indicated only in HCC patients with residual liver function and preserved physical condition [3, 4]. During the course of treatment, cancer cells develop resistance towards functionally and structurally different anticancer drugs by either acquired (due to host factors) or intrinsic (due to genetic or epigenetic) mechanisms [5, 6]. Limited therapeutic effect of Sorafenib could be due to the resistance of cancerous cells to drugs and to the adverse reactions of this molecule. One of the mechanisms of resistance to molecules of chemotherapy is due to decreased absorption of these molecules and their increased efflux via membrane transporters proteins [7]

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Conclusion