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.

TAp63α targeting of Lgr5 mediates colorectal cancer stem cell properties and sulforaphane inhibition

“…The p63 family members are crucial regulators of cancer and have been found to play an important role in embryonic stem cells [25][26][27] . As reported by several studies, TAp63 suppressed the progression of cancers, and thus be considered as a promising strategy for therapeutics 9,10,28 . However, other studies have shown that TAp63 also promoted stem cell maintenance and differentiation 12,13 .…”

The foggy world(s) of p63 isoform regulation in normal cells and cancer

“…Whilst these therapies have other primary targets, their ability to inhibit ΔNp63 suggests that they could be repurposed for therapy of tumours with a ΔNp63 + cell population. Alternatively, inducing TAp63 through miR‐130b has been suggested as a therapeutic option for tumours with mutant p53 [248], although such approaches are not yet clinically available.…”

Pin1 and JNK1 cooperatively modulate TAp63γ

“…Based on these results, we propose the following model to interpret the regulation of TAp63γ transactivity (as shown in Graphical abstract figure): TAp63γ with S 12 unphosphorylated is moderately active; phosphorylation at this residue (pS 12 ) mediated by IKKβ or JNK1 can repress its activity; in the presence of Pin1, isomerization of this pS 12 ‐P 13 motif makes TAp63γ hyperactive. Our data are helpful to elucidate the regulation of TAp63γ, which is an important transcription factor in tumorigenesis and germline quality control, as well as a potential therapeutic target against p53‐altered tumors [10,16].…”

“…Data from Ernesto Bruno group suggest that TAp63 suppresses recurrence of nasal polyps [15]. According to reports from group of Esther H. Chang, miR-130b and TAp63 form a feed-forward loop, and this miR-130b/ TAp63 axis is a druggable pathway that has the potential to uncover broad-spectrum therapeutic options for the majority of p53-altered cancers [16]. It has been reported that TAp63 may also function as a repressor of transcription [17].…”