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A dual role of p21waf1/cip1 gene in apoptosis of HEp-2 treated with cisplatin or methotrexate

Cancer Gene Therapy volume 15, pages 576–590 (2008)Cite this article

Abstract

We investigated the effects of p21waf1/cip1 gene overexpression in human laryngeal squamous carcinoma cells HEp-2 lacking p53 protein expression on apoptosis induction upon the treatment with two commonly used chemotherapeutic agents, cisplatin and methotrexate. For that purpose, we employed cDNA arrays and qPCR to monitor gene expression upon treatment with AdCMV-p21 alone or in combination with the chemotherapeutic compounds. We found that p21waf1/cip1 gene overexpression provoked apoptosis of HEp-2 through the induction of the TNFRSF9 gene and activation of caspase 7. In addition, we have proved that p21waf1/cip1 can assume a dual role in apoptosis in the same cell system depending on the chemotherapeutic agent: its overexpression enhances apoptosis in cisplatin-treated cells and attenuates apoptotic signals in methotrexate-treated cells. The observed dual role of p21waf1/cip1 was in direct correlation with the modulation of caspases 3 and 7 activation and changes in the expression of GADD45a gene. The results presented herein encourage future use of targeted p21waf1/cip1 gene therapy in cancer treatment in a well-defined therapeutic and genetic context.

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Acknowledgements

This paper was financially supported by the Croatian Ministry of Science, Education and Sport's grant ‘The role of genes/proteins transduction on the signaling pathways of transformed cells’ (0098093) and JEZGRE-TEST ‘Centre for integrative genomics, molecular diagnostic, cell and gene therapy’ (14M09800). We thank Marko Marjanovic for the assistance in adenoviral vectors preparation and Dr Mirela Baus-Loncar for useful suggestions in qPCR experimental design and help with qPCR data analysis.

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  1. Division of Molecular Medicine, Laboratory of systems biomedicine, Rudjer Boskovic Institute, Zagreb, Croatia

    S Kraljevic Pavelic

  2. Division of Molecular Medicine, Laboratory of molecular oncology, Rudjer Boskovic Institute, Zagreb, Croatia

    T Cacev

  3. Division of Molecular Medicine, Laboratory of functional genomics, Rudjer Boskovic Institute, Zagreb, Croatia

    M Kralj

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  1. S Kraljevic Pavelic
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Correspondence to S Kraljevic Pavelic or M Kralj.

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Pavelic, S., Cacev, T. & Kralj, M. A dual role of p21waf1/cip1 gene in apoptosis of HEp-2 treated with cisplatin or methotrexate. Cancer Gene Ther 15, 576–590 (2008). https://doi.org/10.1038/cgt.2008.28

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