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Activating p53 family member TAp63: A novel therapeutic strategy for targeting p53‐altered tumors
BACKGROUND: Over 96% of high‐grade ovarian carcinomas and 50% of all cancers are characterized by alterations in the p53 gene. Therapeutic strategies to restore and/or reactivate the p53 pathway have been challenging. By contrast, p63, which shares many of the downstream targets and functions of p53...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617807/ https://www.ncbi.nlm.nih.gov/pubmed/31012964 http://dx.doi.org/10.1002/cncr.32053 |
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author | Gunaratne, Preethi H. Pan, Yinghong Rao, Abhi K. Lin, Chunru Hernandez‐Herrera, Anadulce Liang, Ke Rait, Antonina S. Venkatanarayan, Avinashnarayan Benham, Ashley L. Rubab, Farwah Kim, Sang Soo Rajapakshe, Kimal Chan, Clara K. Mangala, Lingegowda S. Lopez‐Berestein, Gabriel Sood, Anil K. Rowat, Amy C. Coarfa, Cristian Pirollo, Kathleen F. Flores, Elsa R. Chang, Esther H. |
author_facet | Gunaratne, Preethi H. Pan, Yinghong Rao, Abhi K. Lin, Chunru Hernandez‐Herrera, Anadulce Liang, Ke Rait, Antonina S. Venkatanarayan, Avinashnarayan Benham, Ashley L. Rubab, Farwah Kim, Sang Soo Rajapakshe, Kimal Chan, Clara K. Mangala, Lingegowda S. Lopez‐Berestein, Gabriel Sood, Anil K. Rowat, Amy C. Coarfa, Cristian Pirollo, Kathleen F. Flores, Elsa R. Chang, Esther H. |
author_sort | Gunaratne, Preethi H. |
collection | PubMed |
description | BACKGROUND: Over 96% of high‐grade ovarian carcinomas and 50% of all cancers are characterized by alterations in the p53 gene. Therapeutic strategies to restore and/or reactivate the p53 pathway have been challenging. By contrast, p63, which shares many of the downstream targets and functions of p53, is rarely mutated in cancer. METHODS: A novel strategy is presented for circumventing alterations in p53 by inducing the tumor‐suppressor isoform TAp63 (transactivation domain of tumor protein p63) through its direct downstream target, microRNA‐130b (miR‐130b), which is epigenetically silenced and/or downregulated in chemoresistant ovarian cancer. RESULTS: Treatment with miR‐130b resulted in: 1) decreased migration/invasion in HEYA8 cells (p53 wild‐type) and disruption of multicellular spheroids in OVCAR8 cells (p53‐mutant) in vitro, 2) sensitization of HEYA8 and OVCAR8 cells to cisplatin (CDDP) in vitro and in vivo, and 3) transcriptional activation of TAp63 and the B‐cell lymphoma (Bcl)‐inhibitor B‐cell lymphoma 2‐like protein 11 (BIM). Overexpression of TAp63 was sufficient to decrease cell viability, suggesting that it is a critical downstream effector of miR‐130b. In vivo, combined miR‐130b plus CDDP exhibited greater therapeutic efficacy than miR‐130b or CDDP alone. Mice that carried OVCAR8 xenograft tumors and were injected with miR‐130b in 1,2‐dioleoyl‐sn‐glycero‐3‐phosphatidylcholine (DOPC) liposomes had a significant decrease in tumor burden at rates similar to those observed in CDDP‐treated mice, and 20% of DOPC–miR‐130b plus CDDP‐treated mice were living tumor free. Systemic injections of scL–miR‐130b plus CDDP in a clinically tested, tumor‐targeted nanocomplex (scL) improved survival in 60% and complete remissions in 40% of mice that carried HEYA8 xenografts. CONCLUSIONS: The miR‐130b/TAp63 axis is proposed as a new druggable pathway that has the potential to uncover broad‐spectrum therapeutic options for the majority of p53‐altered cancers. |
format | Online Article Text |
id | pubmed-6617807 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-66178072019-07-22 Activating p53 family member TAp63: A novel therapeutic strategy for targeting p53‐altered tumors Gunaratne, Preethi H. Pan, Yinghong Rao, Abhi K. Lin, Chunru Hernandez‐Herrera, Anadulce Liang, Ke Rait, Antonina S. Venkatanarayan, Avinashnarayan Benham, Ashley L. Rubab, Farwah Kim, Sang Soo Rajapakshe, Kimal Chan, Clara K. Mangala, Lingegowda S. Lopez‐Berestein, Gabriel Sood, Anil K. Rowat, Amy C. Coarfa, Cristian Pirollo, Kathleen F. Flores, Elsa R. Chang, Esther H. Cancer Original Articles BACKGROUND: Over 96% of high‐grade ovarian carcinomas and 50% of all cancers are characterized by alterations in the p53 gene. Therapeutic strategies to restore and/or reactivate the p53 pathway have been challenging. By contrast, p63, which shares many of the downstream targets and functions of p53, is rarely mutated in cancer. METHODS: A novel strategy is presented for circumventing alterations in p53 by inducing the tumor‐suppressor isoform TAp63 (transactivation domain of tumor protein p63) through its direct downstream target, microRNA‐130b (miR‐130b), which is epigenetically silenced and/or downregulated in chemoresistant ovarian cancer. RESULTS: Treatment with miR‐130b resulted in: 1) decreased migration/invasion in HEYA8 cells (p53 wild‐type) and disruption of multicellular spheroids in OVCAR8 cells (p53‐mutant) in vitro, 2) sensitization of HEYA8 and OVCAR8 cells to cisplatin (CDDP) in vitro and in vivo, and 3) transcriptional activation of TAp63 and the B‐cell lymphoma (Bcl)‐inhibitor B‐cell lymphoma 2‐like protein 11 (BIM). Overexpression of TAp63 was sufficient to decrease cell viability, suggesting that it is a critical downstream effector of miR‐130b. In vivo, combined miR‐130b plus CDDP exhibited greater therapeutic efficacy than miR‐130b or CDDP alone. Mice that carried OVCAR8 xenograft tumors and were injected with miR‐130b in 1,2‐dioleoyl‐sn‐glycero‐3‐phosphatidylcholine (DOPC) liposomes had a significant decrease in tumor burden at rates similar to those observed in CDDP‐treated mice, and 20% of DOPC–miR‐130b plus CDDP‐treated mice were living tumor free. Systemic injections of scL–miR‐130b plus CDDP in a clinically tested, tumor‐targeted nanocomplex (scL) improved survival in 60% and complete remissions in 40% of mice that carried HEYA8 xenografts. CONCLUSIONS: The miR‐130b/TAp63 axis is proposed as a new druggable pathway that has the potential to uncover broad‐spectrum therapeutic options for the majority of p53‐altered cancers. John Wiley and Sons Inc. 2019-04-23 2019-07-15 /pmc/articles/PMC6617807/ /pubmed/31012964 http://dx.doi.org/10.1002/cncr.32053 Text en © 2019 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | Original Articles Gunaratne, Preethi H. Pan, Yinghong Rao, Abhi K. Lin, Chunru Hernandez‐Herrera, Anadulce Liang, Ke Rait, Antonina S. Venkatanarayan, Avinashnarayan Benham, Ashley L. Rubab, Farwah Kim, Sang Soo Rajapakshe, Kimal Chan, Clara K. Mangala, Lingegowda S. Lopez‐Berestein, Gabriel Sood, Anil K. Rowat, Amy C. Coarfa, Cristian Pirollo, Kathleen F. Flores, Elsa R. Chang, Esther H. Activating p53 family member TAp63: A novel therapeutic strategy for targeting p53‐altered tumors |
title | Activating p53 family member TAp63: A novel therapeutic strategy for targeting p53‐altered tumors |
title_full | Activating p53 family member TAp63: A novel therapeutic strategy for targeting p53‐altered tumors |
title_fullStr | Activating p53 family member TAp63: A novel therapeutic strategy for targeting p53‐altered tumors |
title_full_unstemmed | Activating p53 family member TAp63: A novel therapeutic strategy for targeting p53‐altered tumors |
title_short | Activating p53 family member TAp63: A novel therapeutic strategy for targeting p53‐altered tumors |
title_sort | activating p53 family member tap63: a novel therapeutic strategy for targeting p53‐altered tumors |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617807/ https://www.ncbi.nlm.nih.gov/pubmed/31012964 http://dx.doi.org/10.1002/cncr.32053 |
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