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Granulocyte‐macrophage colony‐stimulating factor stimulates the metastatic properties of lewis lung carcinoma cells through a protein kinase a signal‐transduction pathway
Author(s) -
Young M. Rita I.,
Lozano Yvonne,
Djordjevic Andelka,
Devata Sandeep,
Matthews John,
Young Melvin E.,
Wright Mark A.
Publication year - 1993
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.2910530424
Subject(s) - lewis lung carcinoma , signal transduction , protein kinase a , biology , granulocyte macrophage colony stimulating factor , transfection , cancer research , microbiology and biotechnology , kinase , cell culture , cytokine , immunology , metastasis , cancer , genetics
Expression of granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) by metastatic Lewis lung carcinoma cells (LLC‐ LN7) was previously shown to contribute to the maintenance of phenotypic characteristics associated with an increased capacity to metastasize. In the present study, pre‐incubation of LLC‐LN7 cells with neutralizing anti‐GM‐CSF antibodies diminished the capacity of the tumor cells to form experimental metastases after i.v. inoculation, while pre‐incubation with recombinant GM‐CSF (rGM‐CSF) increased formation of metastases. In the presence of rGM‐CSF, the LLC‐LN7 cells exhibited an increased capacity to migrate, invade through a reconstituted basement membrane, and adhere to lung tissue. Studies to identify the signal transduction pathway through which GM‐CSF enhanced the in vitro metastatic properties of the LLC‐LN7 tumor cells implicated protein kinase A (PKA). Signaling through PKA was suggested by the demonstration that the stimulation of tumor‐cell motility by GM‐CSF was blocked in the presence of the adenylate cyclase inhibitor nicotinic acid, or the PKA inhibitors A3 or KT5720. In addition, the role of PKA as a signaling mechanism for GM‐CSF was assessed by using REV‐LN7 cells, which are LLC‐LN7 cells that have been stably tranrfected with an expression vector encoding a mutant PKA RIα. subunit and which, in turn, express a cAMP‐resistant PKA. Adherence and invasion by the PKA‐defective REV‐LN7 cells were not stimulated by rGM‐CSF, contrasting with the stimulation observed for wild‐type LLC‐LN7 cells. These data suggest that rGM‐CSF can further enhance the in vitro metastatic characteristics of LLC‐LN7 tumor cells and that this is dependent on signal transduction through PKA.