Polyamines regulate human medullary thyroid carcinoma TT-cell proliferation and secretion of calcitonin and calcitonin gene-related peptide.
The significance of polyamines for the neoplastic proliferation and secretion of calcitonin (CT) and calcitonin-gene-related peptide (CGRP) by the human medullary thyroid carcinoma TT cell line was investigated. TT cells were cultured in vitro for 6 days with or without additions of pathway inhibitors of polyamine biosynthetic enzymes. Treatment of the cells with 1 mM of the specific L-ornithine decarboxylase (ODC) inhibitor DL-alpha-difluoromethylornithine (DFMO) resulted in a 97% decrease in ODC activity, lowered contents of putrescine (96%) and spermidine (85%) and cell proliferation rates (90%) along with a compensatory 15-fold increase in S-adenosyl-L-methionine decarboxylase (SAMDC) activity. DFMO treatment also led to a decrease in cellular content of CT (33%) and CGRP (26%), while the drug enhanced secretion of CT (31%) but depressed that of CGRP (26%), and elevated the ratio of CT to CGRP secreted into the medium by 74%. Ethylglyoxal bis(guanylhydrazone) (EGBG), a SAMDC inhibitor, at 100 microM evoked a similar reduction of cell proliferation and lowered the content of spermine by 81%. Furthermore, EGBG treatment caused a 34-fold increase in ODC activity and a subsequent 35-fold build-up of putrescine, but also seemed to stabilize SAMDC as evidenced by a highly enhanced SAMDC activity (approximately 200-fold) during enzyme assays in the absence of the inhibitor. EGBG exposure resulted in an increase in cellular CT content (110%) and secretion of the hormone (82%), while not affecting CGRP content or release.2+ EGBG effects were partially counteracted by DFMO.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Molecular Medicine (L6:02), Karolinska Institute, Karolinska Hospital, Stockholm, Sweden.
A
A
Sjöholm
E
E
Bucht
E
E
Theodorsson
R
R
Larsson
P
P
Nygren
D012437:Adenosylmethionine Decarboxylase / Q000037:antagonists & inhibitors / Q000378:metabolism; D002116:Calcitonin / Q000378:metabolism*; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism*; D018276:Carcinoma, Medullary / Q000473:pathology* / Q000503:physiopathology; D002455:Cell Division / Q000187:drug effects; D000518:Eflornithine / Q000494:pharmacology; D006801:Humans; D008935:Mitoguazone / Q000031:analogs & derivatives / Q000494:pharmacology; D009955:Ornithine Decarboxylase / Q000378:metabolism; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines / Q000378:metabolism*; D011700:Putrescine / Q000378:metabolism; D013095:Spermidine / Q000378:metabolism; D013096:Spermine / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000473:pathology* / Q000503:physiopathology; D014407:Tumor Cells, Cultured
D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines; C041127:ethylglyoxal bis(guanylhydrazone); D013096:Spermine; D002116:Calcitonin; D009955:Ornithine Decarboxylase; D012437:Adenosylmethionine Decarboxylase; D015740:Calcitonin Gene-Related Peptide; D008935:Mitoguazone; D013095:Spermidine; D011700:Putrescine; D000518:Eflornithine