Inhibition of S-adenosylmethionine decarboxylase by inhibitor SAM486A connects polyamine metabolism with p53-Mdm2-Akt/protein kinase B regulation and apoptosis in neuroblastoma.
S-adenosylmethionine decarboxylase (AdoMetDC) is an essential enzyme of polyamine (PA) biosynthesis, and both AdoMetDC and PA levels are often up-regulated in cancer cells. The second-generation inhibitor SAM486A inhibits AdoMetDC enzyme activity and has been evaluated in phase II clinical cancer trials. However, little is known about the mechanism of action and potential use of this therapeutic drug in the treatment of the pediatric cancer neuroblastoma (NB). Here, we show that p53 wild-type NB cells are highly sensitive to SAM486A treatment. Most notably, SAM486A treatment resulted in the rapid accumulation of proapoptotic proteins p53 and Mdm2. Concomitant with the increase of proteins at endogenous levels, the in vivo phosphorylation of p53 at residues Ser(46)/Ser(392) and Mdm2 at residue Ser(166) was observed. Moreover, the antiapoptotic protein Akt/protein kinase B was down-regulated and also dephosphorylated at residue Ser(473) in a dose- and time-dependent manner and NB cells entered apoptotic cell death. The results presented in this study highlight the importance of PA homeostasis and provide a direct link between PA metabolism and apoptotic cell signaling pathways in p53 wild-type NB cells. PA inhibitors such as SAM486A may be effective alternative agents for the treatment of NBs with or without MYCN amplification.
Koomoa
Dana-Lynn T
DL
Cancer Research Center of Hawaii, University of Hawaii at Manoa, Honolulu, HI 96813, USA.
Borsics
Tamas
T
Feith
David J
DJ
Coleman
Craig C
CC
Wallick
Christopher J
CJ
Gamper
Ivonne
I
Pegg
Anthony E
AE
Bachmann
André S
AS
D012437:Adenosylmethionine Decarboxylase / Q000037:antagonists & inhibitors*; D000578:Amidines / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D007189:Indans / Q000494:pharmacology*; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D012436:S-Adenosylmethionine / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000578:Amidines; D000970:Antineoplastic Agents; D007189:Indans; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C082408:4-amidinoindan-1-one 2'-amidinohydrazone; D012436:S-Adenosylmethionine; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D051057:Proto-Oncogene Proteins c-akt; D012437:Adenosylmethionine Decarboxylase