TY - JOUR
T1 - Spermidine/spermine N1-acetyltransferase transient overexpression restores sensitivity of resistant human ovarian cancer cells to N1N12-bis(ethyl)spermine and to cisplatin
AU - Marverti, Gaetano
AU - Monti, Maria Giuseppina
AU - Pegg, Anthony E.
AU - McCloskey, Diane E.
AU - Bettuzzi, Saverio
AU - Ligabue, Alessio
AU - Caporali, Andrea
AU - D'Arca, Domenico
AU - Moruzzi, Maria Stella
N1 - Funding Information:
This work was supported by a grant from MURST 60%, and from Associazione Angela Serra per la Ricerca sul Cancro, Azienda Ospedaliera Policlinico di Modena, Modena, Italy. This work has been also partially supported by PRINN (Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale) 2004, MIUR, Italy and Associazione Assistenza Tumori Alto Adige–Südtiroler Krebshilfe, Bolzano, Italy.
PY - 2005/10
Y1 - 2005/10
N2 - The limited induction of spermidine/spermine N1-acetyltransferase (SSAT) activity has been implicated as an important determinant of the reduced response to the spermine analogue N1,N12-bis(ethyl)spermine (BESpm) by the cisplatin or cis diamminedichloroplatinum(II) (cDDP)- resistant human ovarian carcinoma cell line (C13*). We checked whether or not under conditions of SSAT overexpression, enzyme induction and cell sensitivity to both, BESpm and cDDP, were restored to levels comparable with those of more responsive cDDP-sensitive 2008 cells. We transiently transfected the SSAT repressed C13* cells with two expression vectors driving human SSAT overexpression by diverse promoters. We then analysed their responses in the absence and in the presence of BESpm. SSAT activity was promptly, but briefly, expressed by transfection with both pOP/SSAT and pCMV-SSAT plasmids. However, only in the presence of BESpm, did SSAT activity reach the highest levels of induction for longer duration, with different time-courses for the two vectors, that paralleled the effect on cell growth. Under these conditions, growth sensitivity to BESpm of the less-responsive C13* cells was 25% reverted to cell growth inhibition displayed by 2008 cells. More interestingly, the sensitivity to cDDP cytotoxicity also increased in parallel to SSAT overexpression. BESpm induction of pCMV-SSAT-transfected cells caused a further 20-30% reduction of cell survival induced by cDDP, almost recovering the sensitivity of 2008 cells. The enhanced effectiveness of cDDP was also confirmed by the comet assay, showing an increase in the number and length of tails of damaged DNA. These findings confirm that SSAT overexpression inhibits cell growth and enhances growth sensitivity to BESpm in C13* cells, showing for the first time that restoring high inducibility of SSAT activity subverts the reduced sensitivity to cDDP of SSAT-deficient cells, making them almost indistinguishable from the responsive parental 2008 cells.
AB - The limited induction of spermidine/spermine N1-acetyltransferase (SSAT) activity has been implicated as an important determinant of the reduced response to the spermine analogue N1,N12-bis(ethyl)spermine (BESpm) by the cisplatin or cis diamminedichloroplatinum(II) (cDDP)- resistant human ovarian carcinoma cell line (C13*). We checked whether or not under conditions of SSAT overexpression, enzyme induction and cell sensitivity to both, BESpm and cDDP, were restored to levels comparable with those of more responsive cDDP-sensitive 2008 cells. We transiently transfected the SSAT repressed C13* cells with two expression vectors driving human SSAT overexpression by diverse promoters. We then analysed their responses in the absence and in the presence of BESpm. SSAT activity was promptly, but briefly, expressed by transfection with both pOP/SSAT and pCMV-SSAT plasmids. However, only in the presence of BESpm, did SSAT activity reach the highest levels of induction for longer duration, with different time-courses for the two vectors, that paralleled the effect on cell growth. Under these conditions, growth sensitivity to BESpm of the less-responsive C13* cells was 25% reverted to cell growth inhibition displayed by 2008 cells. More interestingly, the sensitivity to cDDP cytotoxicity also increased in parallel to SSAT overexpression. BESpm induction of pCMV-SSAT-transfected cells caused a further 20-30% reduction of cell survival induced by cDDP, almost recovering the sensitivity of 2008 cells. The enhanced effectiveness of cDDP was also confirmed by the comet assay, showing an increase in the number and length of tails of damaged DNA. These findings confirm that SSAT overexpression inhibits cell growth and enhances growth sensitivity to BESpm in C13* cells, showing for the first time that restoring high inducibility of SSAT activity subverts the reduced sensitivity to cDDP of SSAT-deficient cells, making them almost indistinguishable from the responsive parental 2008 cells.
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U2 - 10.1093/carcin/bgi129
DO - 10.1093/carcin/bgi129
M3 - Article
C2 - 15905201
AN - SCOPUS:27144468971
SN - 0143-3334
VL - 26
SP - 1677
EP - 1686
JO - Carcinogenesis
JF - Carcinogenesis
IS - 10
ER -