RT Journal Article
SR Electronic
T1 Triapine and a More Potent Dimethyl Derivative Induce ER Stress in Cancer Cells
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.113.090605
DO 10.1124/mol.113.090605
A1 Robert Trondl
A1 Lea S. Flocke
A1 Christian R. Kowol
A1 Petra Heffeter
A1 Ute Jungwirth
A1 Georg E. Mair
A1 Ralf Steinborn
A1 Eva A. Enyedy
A1 Michael A. Jakupec
A1 Walter Berger
A1 Bernhard K. Keppler
YR 2013
UL http://molpharm.aspetjournals.org/content/early/2013/12/30/mol.113.090605.abstract
AB Triapine (3-AP), a ribonucleotide reductase inhibitor, has been extensively evaluated in clinical trials in the last decade. This study addresses the role of ER stress in the anticancer activity of 3-AP and the derivative 3-AP-Me, differing from 3-AP only by dimethylation of the terminal nitrogen. Treatment of colon cancer cells with 3-AP or 3-AP-Me activated all three ER stress pathways (PERK, IRE1a and ATF6) by phosphorylation of eIF2α and upregulation of ATF4 and ATF6 gene expression, and particularly 3-AP-Me lead to an upregulation of the alternatively spliced mRNA variant XBP1s (16-fold). Moreover, 3-AP and 3-AP-Me activated the cellular stress kinases JNK and p38 MAPK, and inhibition of JNK activity antagonized the cytotoxic effect of both compounds. Subsequent to induction of the unfolded protein response (UPR), a significant upregulation of pro-apoptotic proteins was detected, including the transcription factor CHOP and the BH3-only member protein Bim, an essential factor for ER stress-related apoptosis. In correlation with the higher degree of ER stress after 3-AP-Me treatment, also a more potent depolarization of mitochondrial membranes was found. These data suggest that 3-AP and 3-AP-Me induce apoptosis via ER stress. This was further corroborated by showing that inhibition of protein biosynthesis with cycloheximide prior to 3-AP and 3-AP-Me treatment leads to a significant reduction of the anti-proliferative properties of both compounds. Taken together, this study demonstrates that induction of ER stress contributes to the mode of action of 3-AP and that terminal methylation leads to an even more pronounced manifestation of this effect.