Several studies in the last years evidenced that deregulation of proapoptotic and antiapoptotic pathways are key players in the onset and maintenance of chemoresistance in advanced ovarian cancers. To characterize the signaling events and molecules involved in the acquisition of cisplatin resistance, we used the human ovarian cancer cell line A2780 and its derivative cisplatin-resistant subline A2780 CIS. We found that the mitochondrial intrinsic apoptotic pathway, induced by cis-dichlorodiammineplatinum (CDDP) in A2780 wild-type cells, was compromised in the resistant subline CIS. The analysis of expression of proteins involved in mitochondria-dependent apoptosis revealed a role of Bax and p73 but not p53. Indeed, we found that CDDP treatment induced the up-regulation of p53 in both sensitive and resistant A2780 cell lines. By contrast, p73 and Bax expressions were compromised in resistant cells. Pretreatment of resistant A2780 CIS cells with the histone deacetylase inhibitor trichostatin A overcomes apoptosis resistance to CDDP by restoring both p73 and Bax but not p53 expression. Altogether, these data indicate that p73, but not p53, is involved in the regulation of apoptosis susceptibility to cisplatin in A2780 ovarian cancer cells and evidence a key contribution of histone deacetylase activation in the acquisition of chemotherapy resistance in human ovarian cancer cells.

Trichostatin A up-regulates p73 and induces Bax-dependent apoptosis in cisplatin-resistant ovarian cancer cells / Muscolini, Michela; R., Cianfrocca; A., Sajeva; S., Mozzetti; G., Ferrandina; A., Costanzo; Tuosto, Loretta. - In: MOLECULAR CANCER THERAPEUTICS. - ISSN 1535-7163. - 7:6(2008), pp. 1410-1419. [10.1158/1535-7163.mct-08-0299]

Trichostatin A up-regulates p73 and induces Bax-dependent apoptosis in cisplatin-resistant ovarian cancer cells

MUSCOLINI, MICHELA;TUOSTO, Loretta
2008

Abstract

Several studies in the last years evidenced that deregulation of proapoptotic and antiapoptotic pathways are key players in the onset and maintenance of chemoresistance in advanced ovarian cancers. To characterize the signaling events and molecules involved in the acquisition of cisplatin resistance, we used the human ovarian cancer cell line A2780 and its derivative cisplatin-resistant subline A2780 CIS. We found that the mitochondrial intrinsic apoptotic pathway, induced by cis-dichlorodiammineplatinum (CDDP) in A2780 wild-type cells, was compromised in the resistant subline CIS. The analysis of expression of proteins involved in mitochondria-dependent apoptosis revealed a role of Bax and p73 but not p53. Indeed, we found that CDDP treatment induced the up-regulation of p53 in both sensitive and resistant A2780 cell lines. By contrast, p73 and Bax expressions were compromised in resistant cells. Pretreatment of resistant A2780 CIS cells with the histone deacetylase inhibitor trichostatin A overcomes apoptosis resistance to CDDP by restoring both p73 and Bax but not p53 expression. Altogether, these data indicate that p73, but not p53, is involved in the regulation of apoptosis susceptibility to cisplatin in A2780 ovarian cancer cells and evidence a key contribution of histone deacetylase activation in the acquisition of chemotherapy resistance in human ovarian cancer cells.
2008
Apoptosis; drug effects, Base Sequence, Caspase 3; metabolism, Cell Line; Tumor, Cisplatin; pharmacology, Cytochromes c; secretion, DNA-Binding Proteins; genetics, Drug Resistance; Neoplasm; drug effects, Drug Screening Assays; Antitumor, Enzyme Activation; drug effects, Female, Humans, Hydroxamic Acids; pharmacology, Membrane Potential; Mitochondrial; drug effects, Mitochondria; drug effects/pathology/secretion, Molecular Sequence Data, Nuclear Proteins; genetics, Ovarian Neoplasms; pathology, Tumor Suppressor Protein p53; metabolism, Tumor Suppressor Proteins; genetics, Up-Regulation; drug effects, bcl-2-Associated X Protein; genetics/metabolism
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Trichostatin A up-regulates p73 and induces Bax-dependent apoptosis in cisplatin-resistant ovarian cancer cells / Muscolini, Michela; R., Cianfrocca; A., Sajeva; S., Mozzetti; G., Ferrandina; A., Costanzo; Tuosto, Loretta. - In: MOLECULAR CANCER THERAPEUTICS. - ISSN 1535-7163. - 7:6(2008), pp. 1410-1419. [10.1158/1535-7163.mct-08-0299]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/359108
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