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Published on: January 7, 2013
Homeodomain-interacting protein kinase-2 activity and p53 phosphorylation are critical events for cisplatin-mediated
Valeria Di Stefano1, Cinzia Rinaldo, Ada Sacchi
1Deparment of Experimental Oncology, Molecular Oncogenesis Laboratory, Regina Elena Cancer Institute, via delle Messi d'Oro 156, 00158 Rome, Italy.
Abstract:
HIPK2 is a member of a novel family of nuclear serine-threonine kinases identified through their ability to interact with the Nkx-1.2 homeoprotein. The physiological role of these kinases is largely unknown, but we have recently reported on the involvement of HIPK2 in the induction of apoptosis of tumor cells after UV stress through p53 phosphorylation and transcriptional activation. Here, we demonstrate that the chemotherapeutic drug cisplatin increases HIPK2 protein expression and its kinase activity, and that HIPK2 is involved in cisplatin-dependent apoptosis. Indeed, induction of HIPK2 and of cell death by cisplatin are efficiently inhibited by the serine-threonine kinase inhibitor SB203580 or the transduction of HIPK2-specific RNA-interfering molecules. HIPK2 gene silencing efficiently reduces the p53-mediated transcriptional activation of apoptotic gene promoters as well as apoptotic cell death after treatment with cisplatin. These findings, along with the involvement of p53 phosphorylation at serine 46 (Ser46) in the transcriptional activation of apoptotic gene promoters, suggest a critical role for HIPK2 in triggering p53-dependent apoptosis in response to the antineoplastic drug cisplatin.
Insights
The homeobox-interacting protein kinase 2 (HIPK2) is crucial for cisplatin-induced tumor cell death. HIPK2 activation triggers p53-dependent apoptosis, offering a potential target for cancer therapy.
Area of Science:
- Molecular Biology
- Cancer Research
- Biochemistry
Background:
- Homeobox-interacting protein kinase 2 (HIPK2) is a nuclear serine-threonine kinase involved in UV-induced apoptosis via p53 phosphorylation.
- The precise role of HIPK2 in response to chemotherapeutic agents remains largely unelucidated.
Purpose of the Study:
- To investigate the role of HIPK2 in cisplatin-induced apoptosis of tumor cells.
- To determine if HIPK2 kinase activity and expression are modulated by cisplatin treatment.
Main Methods:
- Assessing HIPK2 protein expression and kinase activity following cisplatin treatment.
- Utilizing the kinase inhibitor SB203580 and HIPK2-specific RNA interference to block HIPK2 function.
- Evaluating the impact of HIPK2 gene silencing on p53-mediated transcriptional activation and cisplatin-induced apoptosis.
Main Results:
- Cisplatin treatment significantly increased HIPK2 protein expression and kinase activity.
- Inhibition of HIPK2 activity or expression using SB203580 or RNA interference reduced cisplatin-induced cell death.
- HIPK2 gene silencing diminished p53-dependent transcriptional activation of apoptotic genes and subsequent apoptosis.
Conclusions:
- HIPK2 plays a critical role in mediating p53-dependent apoptosis induced by the chemotherapeutic drug cisplatin.
- HIPK2 activation and subsequent p53 phosphorylation at Ser46 are key events in triggering apoptosis in response to cisplatin.
- Targeting HIPK2 may represent a novel therapeutic strategy for enhancing the efficacy of cisplatin-based cancer treatments.
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