Induction of tumor cell resistance to macrophage-mediated lysis by phorbol esters: A postbinding event

Fishman, Marvin A.; Gunther, Gary R.

doi:10.1016/0008-8749(86)90037-7

“…Down-regulation ofthe activity of the receptors for epidermal growth factor by activation of the platelet-derived growth factor receptor or phorbol esters has been documented (33)(34)(35)(36)(37)(38)(39)(40)(41). The possibility that TNF-a receptor function may be similarly down-regulated was suggested by recent work demonstrating that pretreatment of tumor cells by phorbol esters induced resistance to macrophage-mediated cytotoxicity (42), probably due to downregulation ofTNF-a receptors (43,44). To investigate whether the TNF-a receptor was altered in HER2-3 cells as opposed to NIH 3T3 neo/dhfr cells, the binding of "'Mabeled rTNF-a (125I-rTNF-a) was compared between these cell lines.…”

Section: Resultsmentioning

confidence: 99%

Amplified expression of the HER2/ERBB2 oncogene induces resistance to tumor necrosis factor alpha in NIH 3T3 cells.

Hudziak¹,

Lewis²,

Shalaby³

et al. 1988

Proc. Natl. Acad. Sci. U.S.A.

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Functional characterization of oncogene products that induce cellular transformation has progressed rapidly in recent years. However, less is known about the mechanism(s) by which the transformed cells may escape destruction by host immune defenses and form tumors. A recently described oncogene that has an important association with aggressive human breast carcinoma is "HER2," for human epidermal growth factor receptor 2. The oncogene has also been called NGL and human c-erbB-2 (ERBB2). In this paper we show that amplification of HER2 oncogene expression can induce resistance of NIH 3T3 cells to the cytotoxic effects of recombinant tumor necrosis factor alpha (rTNF-alpha) or macrophages. Resistance is accompanied by an increased dissociation constant for rTNF-alpha binding to high-affinity receptors on the HER2-transformed NIH 3T3 cells. The resistance phenotype is independent of transformation since NIH 3T3 cells transformed by the activated human homologue of the Harvey-ras oncogene (HRAS) retain high-affinity binding sites for rTNF-alpha as well as sensitivity to its cytotoxic effects. These results suggest that HER2 may potentiate tumorigenesis by inducing tumor cell resistance to host defense mechanisms.

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“…Several inhibitors of TNF-a activities inhibit phosphorylation of proteins. On the other hand, phorbol esters that activate protein kinase C can induce resistance to killing by macrophages [146]. Protein kinases mav limit sustained cvtodasmic calcium fluxes < I f i r granule secretion from adherent PMN stimulated by TNF-that activate the c&ium-dependent endonuclease [ 1471.…”

Section: Phosphorylation Stepsmentioning

confidence: 99%

The molecular action of tumor necrosis factor‐α

Camussi

¹

,

Albano

²

,

Tetta

³

et al. 1991

European Journal of Biochemistry

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Tumor necrosis factor‐α (TNF‐α) is a polypeptide hormone newly synthesized by different cell types upon stimulation with endotoxin, inflammatory mediators (C5a anaphylatoxin), or cytokines such as interleukin‐1 and, in an autocrine manner, TNF itself. The net biological effect of TNF‐α may vary depending on relative concentration, duration of cell exposure and presence of other mediators which may act in synergism with this cytokine. TNF‐α may be relevant either in pathological events occurring in cachexia and endotoxic shock and inflammation or in beneficial processes such as host defense, immunity and tissue homeostasis. The biological effects of TNF‐α are triggered by the binding to specific cell surface receptors. The formation of TNF‐α‐receptor complex activates a variety of biochemical pathways that include the transduction of the signal at least in part controlled by guanine‐nucleotide‐binding regulatory proteins (G proteins), its amplification through activation of adenyl cyclase, phospholipases and protein kinases with the generation of second messenger pathways. The transduction of selected genes in different cell types determines the characteristics of the cell response to TNF‐α. The full understanding of the molecular mechanisms of TNF‐α will provide the basis for a pharmacological approach intended to inhibit or potentiate selected biological actions of this cytokine.

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“…TNF-a translocates protein kinase C from the cytosol to the membrane fraction in myeloid and lymphoid cell lines I141 -1431, but not in other cells sensitive to TNF-a such as fibroblasts [138,141,1421. On the other hand, phorbol esters that activate protein kinase C can induce resistance to killing by macrophages [146]. TNF-a primers PMN for enhanced protein-kinase-C-dependent responses [76, 1441 by increasing the synthesis of an 82-kDa protein, named as MARKCS (myristoylated, Ala-rich C kinase substratum), which is phosphorylated by protein kinase C [145].…”

Section: Phosphorylation Stepsmentioning

confidence: 99%

The molecular action of tumor necrosis factor-α

Camussi

¹

,

Albano

²

,

Tetta

³

et al. 1991

View full text Add to dashboard Cite

Tumor necrosis factor‐α (TNF‐α) is a polypeptide hormone newly synthesized by different cell types upon stimulation with endotoxin, inflammatory mediators (C5a anaphylatoxin), or cytokines such as interleukin‐1 and, in an autocrine manner, TNF itself. The net biological effect of TNF‐α may vary depending on relative concentration, duration of cell exposure and presence of other mediators which may act in synergism with this cytokine. TNF‐α may be relevant either in pathological events occurring in cachexia and endotoxic shock and inflammation or in beneficial processes such as host defense, immunity and tissue homeostasis. The biological effects of TNF‐α are triggered by the binding to specific cell surface receptors. The formation of TNF‐α‐receptor complex activates a variety of biochemical pathways that include the transduction of the signal at least in part controlled by guanine‐nucleotide‐binding regulatory proteins (G proteins), its amplification through activation of adenyl cyclase, phospholipases and protein kinases with the generation of second messenger pathways. The transduction of selected genes in different cell types determines the characteristics of the cell response to TNF‐α. The full understanding of the molecular mechanisms of TNF‐α will provide the basis for a pharmacological approach intended to inhibit or potentiate selected biological actions of this cytokine.

show abstract

Induction of tumor cell resistance to macrophage-mediated lysis by phorbol esters: A postbinding event

Cited by 8 publications

References 30 publications

Amplified expression of the HER2/ERBB2 oncogene induces resistance to tumor necrosis factor alpha in NIH 3T3 cells.

Amplified expression of the HER2/ERBB2 oncogene induces resistance to tumor necrosis factor alpha in NIH 3T3 cells.

The molecular action of tumor necrosis factor‐α

The molecular action of tumor necrosis factor-α

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