Theophylline-induced apoptosis is paralleled by protein kinase A-dependent tissue transglutaminase activation in cancer cells.
It has been reported that theophylline induces growth inhibition and apoptosis in tumour cells. We report that theophylline induces growth inhibition and apoptosis of several human epithelial tumour cells with an IC:50 of 2.5 mM after 48 h of exposure. Moreover, 2.5 mM theophylline induces the accumulation of cancer cells in S-phase of the cell cycle with a concomitant reduction in the percentage of tumour cells in G(1)/G(0) phase. These effects are paralleled by cytoskeletal remodelling with a consequent redistribution of actin fibers and shape change as demonstrated by fluorescence microscopy. The apoptotic death of tumour cells occurs together with an increase in the expression and activity of the pro-apoptotic enzyme tissue transglutaminase (tTGase). All these effects are promptly antagonized by the specific PKA inhibitor KT5720, suggesting the involvement of cAMP intracellular elevation and, consequently, PKA activation. On the other hand, growth inhibition and tTGase expression and activity are potentiated by retinoic acid, a tTGase inducer. Therefore, a mechanistic model of theophylline action and anti-tumour strategies based on the concomitant use of theophylline and agents that potentiate tTGase activity can be hypothesized.
Caraglia
Michele
M
Department of Biochemistry and Biophysics, Second University of Naples, Via Costantinopoli, Naples, Italy. mcaraglia@yahoo.com
Marra
Monica
M
Giuberti
Gaia
G
D'Alessandro
Anna Maria
AM
Beninati
Simone
S
Lentini
Alessandro
A
Pepe
Stefano
S
Boccellino
Mariarosaria
M
Abbruzzese
Alberto
A
D008841:Actin Cytoskeleton / Q000187:drug effects / Q000648:ultrastructure; D017209:Apoptosis / Q000187:drug effects*; D002227:Carbazoles; D002453:Cell Cycle / Q000187:drug effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D005434:Flow Cytometry; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007624:KB Cells; D008856:Microscopy, Fluorescence; D011758:Pyrroles / Q000494:pharmacology; D013806:Theophylline / Q000494:pharmacology*; D013997:Time Factors; D011503:Transglutaminases / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured
D002227:Carbazoles; D007211:Indoles; D011758:Pyrroles; C057416:KT 5720; D013806:Theophylline; D011503:Transglutaminases; D017868:Cyclic AMP-Dependent Protein Kinases