Control of proteinase expression by phorbol‐ester‐and FOS‐dependent pathways in human non‐small‐cell lung‐cancer cells

Activation of protein kinase C‐(PKC) and Fos/Jun‐dependent signal transduction pathways are thought to be major effects of oncogene action in different tumor systems including human non‐small‐cell lung carcinoma (NSCLC). We have previously shown that the phorbol ester analogue phorbol‐myristate‐acet...

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Veröffentlicht in:International journal of cancer 1997-04, Vol.71 (2), p.275-283
Hauptverfasser: Schuermann, Marcus, Jäger, Robert, Salge, Ursula, Risse‐Hackl, Gundula, Havemann, Klaus, Heidtmann, Hans‐Heinrich
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Sprache:eng
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Zusammenfassung:Activation of protein kinase C‐(PKC) and Fos/Jun‐dependent signal transduction pathways are thought to be major effects of oncogene action in different tumor systems including human non‐small‐cell lung carcinoma (NSCLC). We have previously shown that the phorbol ester analogue phorbol‐myristate‐acetate (PMA), which is a potent activator of PKC, can induce squamous‐type cellular differentiation and the expression of proteinases, such as plasminogen activators and pro‐cathepsin L, in several NSCLC cell lines. To investigate the PMA‐dependent effect on proteinase secretion in more detail, we have now analysed the role of a downstream transmitter of PKC activity in this process, namely Fos, which is part of the AP‐1 transcription factor in the nucleus. We transfected a cell line derived from an undifferentiated squamous‐cell lung carcinoma with different chimeric fos‐extrogen receptor constructs (fox‐ER) which makes selective activation of this transcription factor possible. The resulting clones were treated either with PMA as activator of PKC, or with diethylstilbestrol (DES), an estrogen analogue binding to and thereby activating preformed Fos‐ER molecules. We show that cells treated with either substance undergo similar phenotypic changes (change from cuboidal to spindle‐cell type) and decrease their doubling rates and cloning efficiencies. This is paralleled by the induction of several proteinase genes such as t‐PA, urokinase, and pro‐cathepsins B and L. Contrary to activated PKC, Fos in this system seems to be unable to initiate terminal squamous‐cell differentiation, as assessed by the production of cornified envelopes. It is, however, efficient in the stimulation of neutral or lysosomal proteinase secretion as determined by Western‐blot analysis and zymography. This Fos‐ER expressing system thus seems to be a valuable tool in the molecular dissection of pathways that lead to the activation and secretion of proteinases in NSCLC cells. Int. J. Cancer 71:275–283, 1997. © 1997 Wiley‐Liss, Inc.
ISSN:0020-7136
1097-0215
DOI:10.1002/(SICI)1097-0215(19970410)71:2<275::AID-IJC24>3.0.CO;2-F