Objective. Chemoresistance, due to inhibition of apoptotic response, is the major reason for the failure of anticancer therapies. HIPK2 regulatesp53-apoptotic function via serine-46 (Ser46) phosphorylation and activation of p53 is a key determinant in ovarian cancer cell death. In this studywe determined whether HIPK2 overexpression restored apoptotic response in chemoresistant cancer cells.Methods. Using cisplatin chemosensitive (2008) and chemoresistant (2008C13) ovarian cancer cell lines we compared drug-induced activationof the HIPK2/p53Ser46 apoptotic pathway. The levels of HIPK2, Ser46 phosphorylation, and PARP cleavage were detected by Western blotting.The p53Ser46 apoptotic commitment was evaluated by luciferase assay using the Ser46 specific AIP1 target gene promoter. The apoptoticpathway was detected by caspase-3, -8, and -9 activities.Results. HIPK2 was expressed differently in sensitive versus chemoresistant cells in response to different chemotherapeutic drugs (i.e., cisplatinand adriamycin), though the p53Ser46 apoptotic pathway was not defective in chemoresistant 2008C13 cells. Thus, 2008C13 cells were resistant tocisplatin but sensitive to adriamycin-induced apoptosis through activation of the HIPK2/p53Ser46 pathway. HIPK2 knock-down inhibited theadriamycin-induced apoptosis in 2008C13 cells. Exogenous HIPK2 triggered apoptosis in chemoresistant cells, associated with induction ofp53Ser46-target gene AIP1.Conclusions. HIPK2 is an important regulator of p53 activity in response to a chemotherapeutic drug. These results suggest that different drugactivatedpathways may regulate HIPK2 and that HIPK2/p53Ser46 deregulation is involved in chemoresistance. Exogenous HIPK2 mightrepresent a novel therapeutic approach to circumvent inhibition of apoptosis in treatment of chemoresistant ovarian cancers with wtp53.
Overexpression of HIPK2 circumvents the blockade of apoptosis in chemoresistant ovarian cancer cells
D'Orazi, Gabriella
2008-01-01
Abstract
Objective. Chemoresistance, due to inhibition of apoptotic response, is the major reason for the failure of anticancer therapies. HIPK2 regulatesp53-apoptotic function via serine-46 (Ser46) phosphorylation and activation of p53 is a key determinant in ovarian cancer cell death. In this studywe determined whether HIPK2 overexpression restored apoptotic response in chemoresistant cancer cells.Methods. Using cisplatin chemosensitive (2008) and chemoresistant (2008C13) ovarian cancer cell lines we compared drug-induced activationof the HIPK2/p53Ser46 apoptotic pathway. The levels of HIPK2, Ser46 phosphorylation, and PARP cleavage were detected by Western blotting.The p53Ser46 apoptotic commitment was evaluated by luciferase assay using the Ser46 specific AIP1 target gene promoter. The apoptoticpathway was detected by caspase-3, -8, and -9 activities.Results. HIPK2 was expressed differently in sensitive versus chemoresistant cells in response to different chemotherapeutic drugs (i.e., cisplatinand adriamycin), though the p53Ser46 apoptotic pathway was not defective in chemoresistant 2008C13 cells. Thus, 2008C13 cells were resistant tocisplatin but sensitive to adriamycin-induced apoptosis through activation of the HIPK2/p53Ser46 pathway. HIPK2 knock-down inhibited theadriamycin-induced apoptosis in 2008C13 cells. Exogenous HIPK2 triggered apoptosis in chemoresistant cells, associated with induction ofp53Ser46-target gene AIP1.Conclusions. HIPK2 is an important regulator of p53 activity in response to a chemotherapeutic drug. These results suggest that different drugactivatedpathways may regulate HIPK2 and that HIPK2/p53Ser46 deregulation is involved in chemoresistance. Exogenous HIPK2 mightrepresent a novel therapeutic approach to circumvent inhibition of apoptosis in treatment of chemoresistant ovarian cancers with wtp53.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
