Receptor activity modifying protein-3 mediates the protumorigenic activity of lysyl oxidase-like protein-2.
Lysyl oxidase-like protein-2 (LOXL2) induces epithelial to mesenchymal transition and promotes invasiveness. To understand the mechanisms involved, we examined the effect of LOXL2 overexpression in MCF-7 cells on gene expression. We found that LOXL2 up-regulated the expression of receptor activity modifying protein-3 (RAMP3). Expression of RAMP3 in MDA-MB-231 cells in which LOXL2 expression was inhibited restored vimentin expression, invasiveness, and tumor development. Inhibition of RAMP3 expression in MDA-MB-231 cells mimicked the effects produced by inhibition of LOXL2 expression and was accompanied by inhibition of p38 phosphorylation. LOXL2 overexpression in these cells did not restore invasiveness, suggesting that RAMP3 functions downstream to LOXL2. LOXL2 and RAMP3 are strongly coexpressed in human colon, breast, and gastric carcinomas but not in normal colon or gastric epithelial cells. RAMP3 associates with several G-protein-coupled receptors forming receptors for peptides, such as adrenomedullin and amylin. We hypothesized that RAMP3 could function as a transducer of autocrine signals induced by such peptides. However, the proinvasive effects of RAMP3 could not be abrogated following inhibition of the expression or activity of these peptides. Our experiments suggest that the protumorigenic effects of LOXL2 are partially mediated by RAMP3 and that RAMP3 inhibitors may function as antitumorigenic agents. -
Brekhman
Vera
V
Cancer Research and Vascular Biology Center, The Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, 31096, Israel.
Lugassie
Jennie
J
Zaffryar-Eilot
Shelly
S
Sabo
Edmond
E
Kessler
Ofra
O
Smith
Victoria
V
Golding
Hana
H
Neufeld
Gera
G
D000594:Amino Acid Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011485:Protein Binding; D034622:RNA Interference; D058264:Receptor Activity-Modifying Protein 3 / Q000235:genetics* / Q000378:metabolism; D058265:Receptors, Adrenomedullin / Q000235:genetics / Q000378:metabolism; D058287:Receptors, Islet Amyloid Polypeptide / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays
C545504:RAMP3 protein, human; D058264:Receptor Activity-Modifying Protein 3; D058265:Receptors, Adrenomedullin; D058287:Receptors, Islet Amyloid Polypeptide; D000594:Amino Acid Oxidoreductases; C119091:LOXL2 protein, human