Interference with Activator Protein-2 transcription factors leads to induction of apoptosis and an increase in chemo- and radiation-sensitivity in breast cancer cells

<p>Abstract</p> <p>Background</p> <p>Activator Protein-2 (AP-2) transcription factors are critically involved in a variety of fundamental cellular processes such as proliferation, differentiation and apoptosis and have also been implicated in carcinogenesis. Expression of the family members AP-2α and AP-2γ is particularly well documented in malignancies of the female breast. Despite increasing evaluation of single AP-2 isoforms in mammary tumors the functional role of concerted expression of multiple AP-2 isoforms in breast cancer remains to be elucidated. AP-2 proteins can form homo- or heterodimers, and there is growing evidence that the net effect whether a cell will proliferate, undergo apoptosis or differentiate is partly dependent on the balance between different AP-2 isoforms.</p> <p>Methods</p> <p>We simultaneously interfered with all AP-2 isoforms expressed in ErbB-2-positive murine N202.1A breast cancer cells by conditionally over-expressing a dominant-negative AP-2 mutant.</p> <p>Results</p> <p>We show that interference with AP-2 protein function lead to reduced cell number, induced apoptosis and increased chemo- and radiation-sensitivity. Analysis of global gene expression changes upon interference with AP-2 proteins identified 139 modulated genes (90 up-regulated, 49 down-regulated) compared with control cells. Gene Ontology (GO) investigations for these genes revealed <it>Cell Death </it>and <it>Cell Adhesion and Migration </it>as the main functional categories including 25 and 12 genes, respectively. By using information obtained from Ingenuity Pathway Analysis Systems we were able to present proven or potential connections between AP-2 regulated genes involved in cell death and response to chemo- and radiation therapy, (i.e. <it>Ctgf, Nrp1</it>, <it>Tnfaip3, Gsta3</it>) and AP-2 and other main apoptosis players and to create a unique network.</p> <p>Conclusions</p> <p>Expression of AP-2 transcription factors in breast cancer cells supports proliferation and contributes to chemo- and radiation-resistance of tumor cells by impairing the ability to induce apoptosis. Therefore, interference with AP-2 function could increase the sensitivity of tumor cells towards therapeutic intervention.</p

Electrochemically induced transformations of bi- and trinuclear heterometallic vinylidene complexes containing Re, Pd and Fe

Redox-induced transformations of bi-Cp(CO)2RePd(μ-Cdouble bond; length as m-dashCHPh)(PPh3)2 (2), Cp(CO)2RePd(μ-Cdouble bond; length as m-dashCHPh)(P-P) [P-P = η2-Ph2P(CH2)2PPh2 (dppe) (3), η2-Ph2P(CH2)3PPh2 (dppp) (4)], Cp(CO)2ReFe(μ-Cdouble bond; length as m-dashCHPh)(CO)4 (5) and trinuclear Cp(CO)2ReFe2(μ3-Cdouble bond; length as m-dashCHPh)(CO)6 (6), CpReFePd(µ3-Cdouble bond; length as m-dashCHPh)(CO)5(P-P) [P-P = dppe (7), dppp (8)] heterometallic vinylidene complexes derived from Cp(CO)2Redouble bond; length as m-dashCdouble bond; length as m-dashCHPh (1) were investigated by electrochemical methods. The oxidation processes of clusters 7 and 8 were studied by EPR spectroscopy. The electrochemical properties of clusters 7 and 8 were shown to depend on the nature of the chelate diphosphine ligand at the palladium center in contrast to complexes 3 and 4. The oxidation of complexes 2–4 was found to result in the Re-Pd, Pd-C bond cleavage and formation of rhenium complex 1 and Pd-containing fragments. The oxidation of 7 and 8 resulted in the formation of the radical cations 7+radical dot and 8+radical dot, which sequentially transformed into a number of intermediate products: Cp(CO)2RePd(μ-Cdouble bond; length as m-dashCHPh)(P-P), [Fe(CO)3]+radical dot, [CpReFe2(µ3-Cdouble bond; length as m-dashCHPh)(CO)6]+radical dot and others. The final products of their oxidation in both cases were triangular clusters (CO)8Fe2Pd(P-P) [P-P = dppe (9), dppp (10)] and rhenium complex 1. The molecular structure of cluster 7 was established by X-ray diffraction analysis

Electrochemically induced transformations of bi- and trinuclear heterometallic vinylidene complexes containing Re, Pd and Fe

Redox-induced transformations of bi-Cp(CO)2RePd(μ-Cdouble bond; length as m-dashCHPh)(PPh3)2 (2), Cp(CO)2RePd(μ-Cdouble bond; length as m-dashCHPh)(P-P) [P-P = η2-Ph2P(CH2)2PPh2 (dppe) (3), η2-Ph2P(CH2)3PPh2 (dppp) (4)], Cp(CO)2ReFe(μ-Cdouble bond; length as m-dashCHPh)(CO)4 (5) and trinuclear Cp(CO)2ReFe2(μ3-Cdouble bond; length as m-dashCHPh)(CO)6 (6), CpReFePd(µ3-Cdouble bond; length as m-dashCHPh)(CO)5(P-P) [P-P = dppe (7), dppp (8)] heterometallic vinylidene complexes derived from Cp(CO)2Redouble bond; length as m-dashCdouble bond; length as m-dashCHPh (1) were investigated by electrochemical methods. The oxidation processes of clusters 7 and 8 were studied by EPR spectroscopy. The electrochemical properties of clusters 7 and 8 were shown to depend on the nature of the chelate diphosphine ligand at the palladium center in contrast to complexes 3 and 4. The oxidation of complexes 2–4 was found to result in the Re-Pd, Pd-C bond cleavage and formation of rhenium complex 1 and Pd-containing fragments. The oxidation of 7 and 8 resulted in the formation of the radical cations 7+radical dot and 8+radical dot, which sequentially transformed into a number of intermediate products: Cp(CO)2RePd(μ-Cdouble bond; length as m-dashCHPh)(P-P), [Fe(CO)3]+radical dot, [CpReFe2(µ3-Cdouble bond; length as m-dashCHPh)(CO)6]+radical dot and others. The final products of their oxidation in both cases were triangular clusters (CO)8Fe2Pd(P-P) [P-P = dppe (9), dppp (10)] and rhenium complex 1. The molecular structure of cluster 7 was established by X-ray diffraction analysis

Chemistry of vinylidene complexes. XXV. Synthesis and reactions of binuclear μ-vinylidene RePt complexes containing phosphite ligands. Spectroscopic, structural and electrochemical study

Reactions of Cp(CO)(2)Re=C=CHPh with Pt[P(OR)(3)](4) (R = Pr-i, Et, Ph) gave binuclear mu-vinylidene complexes Cp(CO)(2)RePt(mu-C=CHPWW(OR)(3)](2). Treatment of the previously synthesized Cp(CO)(2)Re(mu-C=CHPh)Pt(PPh3)(2) with triisopropylphosphite or triethylphosphite resulted in a stepwise substitution of PPh3 ligands, leading to the disubstituted Cp(CO)(2)RePt(mu-C=CHPh)[P(OR)(3)](2) and monosubstituted Cp(CO)(2)RePt(mu-C=CHPh)[P(OR)(3)] (PPh3) (R = Pr-i or Et) species, while no triphenylphosphine ligand substitution in the reaction with P(OPh)(3) occurs at all. The monosubstituted Cp(CO)(2)RePt(mu-C=CHPh)IP(OR)(3)](PPh3) (R = Pe(i), Et, Ph) species were also obtained by reacting Cp(CO)(2)Re=C=CHPh with mixed-ligand complexes Pt(PPh3)(3)L (L = P(OPi)(3), P(OEt)(3), P (OPh)(3)). Reactions of Cp(CO)(2)RePt(mu-C=CHPh)LL' = L' = P(OPri)(3), P(OEt)(3), P(OPh)(3); L = P(OPri)(3), P(OEt)(3), P(OPh)(3), L' = PPh3) with Co-2(CO)(9) yield tricarbonyl vinylidene species Cp(CO)(2)RePt(mu-C=CHPh)IP(OR)(3)](CO) (R = Pr-i, Et, Ph). The obtained compounds were characterized by IR and H-1, C-13, P-31 NMR spectroscopy. The molecular structures of Cp(CO)(2)RePt(mu-C=CHPh)[P(OPi)(3)](2), Cp(CO)(2)RePt(mu-C=CHPh)[P(OPri)(3)](PPh3) and Cp(CO)(2)RePt(mu-C=CHPh)[P(OPri)(3)](CO) were determined by X-ray diffraction study. The redox properties of the new complexes and their reactions of chemical oxidation were studied