Activating p53 family member TAp63: A novel therapeutic strategy for targeting p53-altered tumors.

TitleActivating p53 family member TAp63: A novel therapeutic strategy for targeting p53-altered tumors.
Publication TypeJournal Article
Year of Publication2019
AuthorsGunaratne, PH, Pan, Y, Rao, AK, Lin, C, Hernandez-Herrera, A, Liang, K, Rait, AS, Venkatanarayan, A, Benham, AL, Rubab, F, Kim, SSoo, Rajapakshe, K, Chan, CK, Mangala, LS, Lopez-Berestein, G, Sood, AK, Rowat, AC, Coarfa, C, Pirollo, KF, Flores, ER, Chang, EH
JournalCancer
Volume125
Issue14
Pagination2409-2422
Date Published2019 07 15
ISSN1097-0142
KeywordsAnimals, Antineoplastic Agents, Binding Sites, Cell Line, Tumor, Cell Movement, Cisplatin, Drug Resistance, Neoplasm, Female, Humans, Liposomes, Mice, Mice, Nude, MicroRNAs, Mutation, Missense, Neoplasm Invasiveness, Ovarian Neoplasms, Protein Isoforms, Signal Transduction, Transcription Factors, Transcriptional Activation, Transfection, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, Xenograft Model Antitumor Assays
Abstract

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.

DOI10.1002/cncr.32053
Alternate JournalCancer
PubMed ID31012964
PubMed Central IDPMC6617807
Grant ListP30 CA016672 / CA / NCI NIH HHS / United States
R01 CA160394 / CA / NCI NIH HHS / United States
T32 CA009686 / CA / NCI NIH HHS / United States
R01 CA218025 / CA / NCI NIH HHS / United States
R35 CA197452 / CA / NCI NIH HHS / United States
R01 CA132012 / CA / NCI NIH HHS / United States
R00 DK094981 / DK / NIDDK NIH HHS / United States