Opposite roles of metastasin (S100A4) in two potentially tumoricidal mechanisms involving human lymphocyte protein Tag7 and Hsp70.
We compare the physical and functional interactions between three widespread multifunctional proteins [metastasin (Mts1/S100A4), innate immunity-related Tag7/PGRP-S, and Hsp70] in two experimental models relevant to host-tumor relationships on humoral and cellular levels. (i) Tag7 and Hsp70 in solution or in a lymphocyte make a stable binary complex that is highly cytotoxic for some tumor cells. Here, we show that Mts1 prevents Tag7.Hsp70 assembly in solution, and an excess of Mts1 disrupts the existing Tag7.Hsp70 complex; accordingly, Tag7.Hsp70 cytotoxicity (exemplified with L929 cells) is diminished in the presence of excess Mts1. (ii) Tag7 exposed on a specialized subset of lymphokine-activated killer cells makes specific contact with Hsp70 exposed on some HLA-negative tumor cells, thus enabling FasL/Fas-mediated induction of apoptosis. Here, we show that some CD4(+)CD25(+) cells coexpose Mts1 with Tag7 and FasL, that Mts1 and Tag7 closely contact the same Hsp70 molecule on the target K562 cell (as evidenced by cross-linking), and that killing of such targets is abolished by Mts1-specific antibodies (or selective removal of Mts1-exposing lymphocytes). Thus, this phenotype active against immunoevasive cancerous cells is defined as CD4(+)CD25(+), FasL(+), Tag7(+)Mts1(+) (approximately 0.5% of total lymphocytes in culture). Remarkably, similar effectors with at least the same activity are often found in fresh donor blood samples (approximately 10(4) effectors/mL). Thus, our models suggest that interactions between the three proteins in different situations may have opposite functional outcomes as regards antitumor defense, immune escape, and metastasis.
Dukhanina
Elena A
EA
Laboratory of Molecular Immunogenetics of Cancer, Institute of Gene Biology, Russian Academy of Sciences, University of Oslo, 34/5 Vavilova Street, Moscow 119334, Russia.
Kabanova
Olga D
OD
Lukyanova
Tamara I
TI
Shatalov
Yury V
YV
Yashin
Denis V
DV
Romanova
Elena A
EA
Gnuchev
Nikolai V
NV
Galkin
Alexander V
AV
Georgiev
Georgii P
GP
Sashchenko
Lidia P
LP
D000818:Animals; D019921:Biotinylation; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D020014:K562 Cells; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D051379:Mice; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000096:biosynthesis / Q000502:physiology*
D016207:Cytokines; D018840:HSP70 Heat-Shock Proteins; D053645:Interleukin-2 Receptor alpha Subunit; C491878:PGLYRP1 protein, human; C113582:Pglyrp1 protein, mouse; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C470944:S100a4 protein, mouse; C077591:S100A4 protein, human