A novel localization of the G-protein-coupled CysLT1 receptor in the nucleus of colorectal adenocarcinoma cells.
Searching for a link between inflammation and colon cancer, we have found that the inflammatory mediator leukotriene D(4) (LTD(4)), via its receptor CysLT(1), induces cyclooxygenase-2 expression, survival, and proliferation in intestinal epithelial cells. In conjunction with our previous observation that CysLT(1) receptor expression is increased in colorectal adenocarcinomas, we here found an increased nuclear localization of the CysLT(1) receptor in colorectal adenocarcinomas. This novel discovery of CysLT(1) receptors in the nucleus was further analyzed. It was found to be located in the outer nuclear membrane in colon cancer cells and in the nontransformed epithelial cell line Int 407 cells by Western blot and electron microscopy. Cancer cells displayed higher amounts of the nuclear CysLT(1) receptor, but prolonged LTD(4) exposure induced its nuclear translocation in nontransformed cells. Truncation of a nuclear localization sequence abrogated this translocation as well as the LTD(4)-induced proliferative response. In accordance, nuclear CysLT(1) receptors exhibited proliferative extracellular signal-regulated kinase 1/2 signaling. The significance of these experimental findings is supported by the observed correlation between the proliferative marker Ki-67 and nuclear CysLT(1) receptor localization in colorectal adenocarcinomas. The present findings indicate that LTD(4) cannot only be synthesized but also signal proliferation through nuclear CysLT(1) receptors, stressing the importance of leukotrienes in inflammation-induced colon carcinogenesis.
Nielsen
Christian Kamp
CK
Division of Experimental Pathology, Department of Laboratory Medicine, Lund University, Malmö University Hospital, SE-205 02 Malmö, Sweden.
Campbell
Joan I A
JI
Ohd
John F
JF
Mörgelin
Matthias
M
Riesbeck
Kristian
K
Landberg
Göran
G
Sjölander
Anita
A
D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000201:enzymology / Q000378:metabolism; D002467:Cell Nucleus / Q000201:enzymology / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017998:Leukotriene D4 / Q000494:pharmacology; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D019913:Nuclear Localization Signals / Q000378:metabolism*; D018077:Receptors, Leukotriene / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D008565:Membrane Proteins; D019913:Nuclear Localization Signals; D018077:Receptors, Leukotriene; D017998:Leukotriene D4; D001094:Arachidonate 5-Lipoxygenase; C083169:leukotriene D4 receptor