Dataset Information

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

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.

SUBMITTER: Gunaratne PH

PROVIDER: S-EPMC6617807 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Publications

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

Gunaratne Preethi H PH Pan Yinghong Y Rao Abhi K AK Lin Chunru C Hernandez-Herrera Anadulce A Liang Ke K Rait Antonina S AS Venkatanarayan Avinashnarayan A Benham Ashley L AL Rubab Farwah F Kim Sang Soo SS Rajapakshe Kimal K Chan Clara K CK Mangala Lingegowda S LS Lopez-Berestein Gabriel G Sood Anil K AK Rowat Amy C AC Coarfa Cristian C Pirollo Kathleen F KF Flores Elsa R ER Chang Esther H EH

Cancer 20190423 14

<h4>Background</h4>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.<h4>Methods</h4>A novel strategy is presented for circumventing alterations in p53 by inducing the tumor-suppressor isoform TAp63 (transactivation domain of tumor ...[more]

PMID: 31012964

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Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

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