Activating P53 Family Member TAp63: A Novel Therapeutic Strategy for Targeting P53-altered Tumors

Overview

Journal Cancer

Publisher Wiley

Specialty Oncology

Date 2019 Apr 24

PMID 31012964

Citations 10

Authors

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

Affiliations

Soon will be listed here.

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.

Citing Articles

How MicroRNAs Command the Battle against Cancer.

Wu H, Leng S, Sergi C, Leng R Int J Mol Sci. 2024; 25(11).

PMID: 38892054 PMC: 11172831. DOI: 10.3390/ijms25115865.

Role of non‑coding RNAs in UV‑induced radiation effects (Review).

Liang X, Zhang C, Shen L, Ding L, Guo H Exp Ther Med. 2024; 27(6):262.

PMID: 38756908 PMC: 11097301. DOI: 10.3892/etm.2024.12550.

Liposomal delivery of gene therapy for ovarian cancer: a systematic review.

Son J, Chow R, Kim H, Lieu T, Xiao M, Kim S Reprod Biol Endocrinol. 2023; 21(1):75.

PMID: 37612696 PMC: 10464441. DOI: 10.1186/s12958-023-01125-2.

Metal-Based Anticancer Complexes and p53: How Much Do We Know?.

Alfadul S, Matnurov E, Varakutin A, Babak M Cancers (Basel). 2023; 15(10).

PMID: 37345171 PMC: 10216058. DOI: 10.3390/cancers15102834.

DNA Demethylation Switches Oncogenic ΔNp63 to Tumor Suppressive TAp63 in Squamous Cell Carcinoma.

Pokorna Z, Hrabal V, Tichy V, Vojtesek B, Coates P Front Oncol. 2022; 12:924354.

PMID: 35912167 PMC: 9331744. DOI: 10.3389/fonc.2022.924354.

References

Gutierrez-Puente Y, Tari A, Stephens C, Rosenblum M, Guerra R, Lopez-Berestein G . Safety, pharmacokinetics, and tissue distribution of liposomal P-ethoxy antisense oligonucleotides targeted to Bcl-2. J Pharmacol Exp Ther. 1999; 291(2):865-9. View

Fang L, Lee S, Aaronson S . Comparative analysis of p73 and p53 regulation and effector functions. J Cell Biol. 1999; 147(4):823-30. PMC: 2156169. DOI: 10.1083/jcb.147.4.823. View

Jung M, Yun J, Chae H, Kim J, Kim S, Choi T . p53 and its homologues, p63 and p73, induce a replicative senescence through inactivation of NF-Y transcription factor. Oncogene. 2001; 20(41):5818-25. DOI: 10.1038/sj.onc.1204748. View

Xu L, Huang C, Huang W, Tang W, Rait A, Yin Y . Systemic tumor-targeted gene delivery by anti-transferrin receptor scFv-immunoliposomes. Mol Cancer Ther. 2002; 1(5):337-46. View

Rait A, Pirollo K, Ulick D, Cullen K, Chang E . HER-2-targeted antisense oligonucleotide results in sensitization of head and neck cancer cells to chemotherapeutic agents. Ann N Y Acad Sci. 2004; 1002:78-89. DOI: 10.1196/annals.1281.018. View

Cannistra S . Cancer of the ovary. N Engl J Med. 2004; 351(24):2519-29. DOI: 10.1056/NEJMra041842. View

Landen Jr C, Chavez-Reyes A, Bucana C, Schmandt R, Deavers M, Lopez-Berestein G . Therapeutic EphA2 gene targeting in vivo using neutral liposomal small interfering RNA delivery. Cancer Res. 2005; 65(15):6910-8. DOI: 10.1158/0008-5472.CAN-05-0530. View

Lin X, Howell S . DNA mismatch repair and p53 function are major determinants of the rate of development of cisplatin resistance. Mol Cancer Ther. 2006; 5(5):1239-47. DOI: 10.1158/1535-7163.MCT-05-0491. View

Suh E, Yang A, Kettenbach A, Bamberger C, Michaelis A, Zhu Z . p63 protects the female germ line during meiotic arrest. Nature. 2006; 444(7119):624-8. DOI: 10.1038/nature05337. View

10.

Ventura A, Kirsch D, McLaughlin M, Tuveson D, Grimm J, Lintault L . Restoration of p53 function leads to tumour regression in vivo. Nature. 2007; 445(7128):661-5. DOI: 10.1038/nature05541. View

11.

Pirollo K, Rait A, Zhou Q, Hwang S, Dagata J, Zon G . Materializing the potential of small interfering RNA via a tumor-targeting nanodelivery system. Cancer Res. 2007; 67(7):2938-43. DOI: 10.1158/0008-5472.CAN-06-4535. View

12.

Yamada K, Cukierman E . Modeling tissue morphogenesis and cancer in 3D. Cell. 2007; 130(4):601-10. DOI: 10.1016/j.cell.2007.08.006. View

13.

Sorrentino A, Liu C, Addario A, Peschle C, Scambia G, Ferlini C . Role of microRNAs in drug-resistant ovarian cancer cells. Gynecol Oncol. 2008; 111(3):478-86. DOI: 10.1016/j.ygyno.2008.08.017. View

14.

Brosh R, Rotter V . When mutants gain new powers: news from the mutant p53 field. Nat Rev Cancer. 2009; 9(10):701-13. DOI: 10.1038/nrc2693. View

15.

Gonfloni S, Di Tella L, Caldarola S, Cannata S, Klinger F, Di Bartolomeo C . Inhibition of the c-Abl-TAp63 pathway protects mouse oocytes from chemotherapy-induced death. Nat Med. 2009; 15(10):1179-85. DOI: 10.1038/nm.2033. View

16.

Guo X, Keyes W, Papazoglu C, Zuber J, Li W, Lowe S . TAp63 induces senescence and suppresses tumorigenesis in vivo. Nat Cell Biol. 2009; 11(12):1451-7. PMC: 2920298. DOI: 10.1038/ncb1988. View

17.

Creighton C, Benham A, Zhu H, Khan M, Reid J, Nagaraja A . Discovery of novel microRNAs in female reproductive tract using next generation sequencing. PLoS One. 2010; 5(3):e9637. PMC: 2835764. DOI: 10.1371/journal.pone.0009637. View

18.

Dotsch V, Bernassola F, Coutandin D, Candi E, Melino G . p63 and p73, the ancestors of p53. Cold Spring Harb Perspect Biol. 2010; 2(9):a004887. PMC: 2926756. DOI: 10.1101/cshperspect.a004887. View

19.

Belyi V, Ak P, Markert E, Wang H, Hu W, Puzio-Kuter A . The origins and evolution of the p53 family of genes. Cold Spring Harb Perspect Biol. 2010; 2(6):a001198. PMC: 2869528. DOI: 10.1101/cshperspect.a001198. View

20.

Su X, Chakravarti D, Cho M, Liu L, Gi Y, Lin Y . TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs. Nature. 2010; 467(7318):986-90. PMC: 3055799. DOI: 10.1038/nature09459. View