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- Title
Activating p53 family member TAp63: A novel therapeutic strategy for targeting p53-altered tumors.
- Authors
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.
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusions: </bold>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.
- Subjects
TUMOR proteins; P53 antioncogene; P53 protein; TUMORS; THERAPEUTICS; OVARIAN cancer; RNA metabolism; PROTEIN metabolism; THERAPEUTIC use of antineoplastic agents; PROTEINS; BINDING sites; ARTIFICIAL membranes; RESEARCH; GENETIC mutation; OVARIAN tumors; CANCER invasiveness; ANIMAL experimentation; RESEARCH methodology; RNA; ANTINEOPLASTIC agents; EVALUATION research; MEDICAL cooperation; CELLULAR signal transduction; CELL motility; COMPARATIVE studies; GENES; CISPLATIN; RESEARCH funding; TRANSCRIPTION factors; GENETIC techniques; CELL lines; MICE; DRUG resistance in cancer cells; PHARMACODYNAMICS
- Publication
Cancer (0008543X), 2019, Vol 125, Issue 14, p2409
- ISSN
0008-543X
- Publication type
journal article
- DOI
10.1002/cncr.32053