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

Cancer. 2019 Jul 15;125(14):2409-2422. doi: 10.1002/cncr.32053. Epub 2019 Apr 23.

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.

Keywords: 3-dimensional (3D) spheroids; B-cell lymphoma 2-like protein 11 (BIM); chemosensitization; cisplatin; leoyl-sn-glycero-3-phosphatidylcholine (DOPC); microRNA 130b (miR-130b); ovarian cancer; transactivation (TA) and N-terminally truncated (ΔN) isoforms of the p63 protein (TAp63/ΔNp63); tumor protein p53; tumor-targeted nanocomplex (scL).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Binding Sites
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cisplatin / pharmacology
  • Cisplatin / therapeutic use
  • Drug Resistance, Neoplasm / drug effects
  • Female
  • Humans
  • Liposomes
  • Mice
  • Mice, Nude
  • MicroRNAs / administration & dosage
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • MicroRNAs / therapeutic use*
  • Mutation, Missense*
  • Neoplasm Invasiveness / prevention & control
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / genetics*
  • Protein Isoforms / genetics
  • Signal Transduction / drug effects
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transcriptional Activation / genetics*
  • Transfection
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Liposomes
  • MIRN130 microRNA, human
  • MicroRNAs
  • Protein Isoforms
  • TP53 protein, human
  • TP63 protein, human
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Cisplatin