Hepatocyte SLAMF3 reduced specifically the multidrugs resistance protein MRP-1 and increases HCC cells sensitization to anti-cancer drugs
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Grégory Fouquet1,*, Véronique Debuysscher1,*, Hakim Ouled-Haddou2,*, Mélanie Simoes Eugenio1, Baptiste Demey1, Amrathlal Rabbind Singh5, Christèle Ossart3, Mohammed Al Bagami2, Jean-Marc Regimbeau4, Eric Nguyen-Khac1,6, Mickael Naassila1, Ingrid Marcq1,*, Hicham Bouhlal1,3,*
1INSERM-ERi 24 (GRAP) Centre Universitaire de Recherche en Santé CURS, Université de Picardie Jules Verne, Cellulaire Centre Hospitalier Universitaire Sud, Amiens, France
2EA 4666 LNPC, Centre Universitaire de Recherche en Santé CURS, CAP-Santé (FED 4231) Cellulaire Centre Hospitalier Universitaire Sud, Amiens, France
3Service de Thérapie Cellulaire Centre Hospitalier Universitaire Sud, Amiens, France
4Service de Chirurgie Digestive Centre Hospitalier Universitaire Sud, Amiens, France
5Department of Microbiology, Dr. G. Venkataswamy Eye Research Institute, Aravind Medical Research Foundation, Madurai, India
6Service Hépato-Gastroenterologie, Centre Hospitalier Universitaire Sud, Amiens, France
*These authors have contributed equally to this work
Hicham Bouhlal, email: [email protected]
Ingrid Marcq, email: [email protected]
Amrathlal Rabbind Singh, email: [email protected]
Keywords: SLAMF3, drugs sensitization, MRP-1, HCC, multidrug resistance
Received: December 21, 2015 Accepted: March 28, 2016 Published: April 11, 2016
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.
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