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

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

Cancer (2019-04-24)
Preethi H Gunaratne, Yinghong Pan, Abhi K Rao, Chunru Lin, Anadulce Hernandez-Herrera, Ke Liang, Antonina S Rait, Avinashnarayan Venkatanarayan, Ashley L Benham, Farwah Rubab, Sang Soo Kim, Kimal Rajapakshe, Clara K Chan, Lingegowda S Mangala, Gabriel Lopez-Berestein, Anil K Sood, Amy C Rowat, Cristian Coarfa, Kathleen F Pirollo, Elsa R Flores, Esther H Chang
摘要

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. 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. 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. 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.

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p53(Ab-3)(突变型)小鼠单克隆抗体(PAb240), liquid, clone PAb240, Calbiochem®