TY - JOUR
T1 - Activating p53 family member TAp63
T2 - A novel therapeutic strategy for targeting p53-altered tumors
AU - Gunaratne, Preethi H.
AU - Pan, Yinghong
AU - Rao, Abhi K.
AU - Lin, Chunru
AU - Hernandez-Herrera, Anadulce
AU - Liang, Ke
AU - Rait, Antonina S.
AU - Venkatanarayan, Avinashnarayan
AU - Benham, Ashley L.
AU - Rubab, Farwah
AU - Kim, Sang Soo
AU - Rajapakshe, Kimal
AU - Chan, Clara K.
AU - Mangala, Lingegowda S.
AU - Lopez-Berestein, Gabriel
AU - Sood, Anil K.
AU - Rowat, Amy C.
AU - Coarfa, Cristian
AU - Pirollo, Kathleen F.
AU - Flores, Elsa R.
AU - Chang, Esther H.
N1 - Publisher Copyright:
© 2019 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society
PY - 2019/7/15
Y1 - 2019/7/15
N2 - 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.
AB - 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.
KW - 3-dimensional (3D) spheroids
KW - B-cell lymphoma 2-like protein 11 (BIM)
KW - chemosensitization
KW - cisplatin
KW - leoyl-sn-glycero-3-phosphatidylcholine (DOPC)
KW - microRNA 130b (miR-130b)
KW - ovarian cancer
KW - transactivation (TA) and N-terminally truncated (ΔN) isoforms of the p63 protein (TAp63/ΔNp63)
KW - tumor protein p53
KW - tumor-targeted nanocomplex (scL)
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U2 - 10.1002/cncr.32053
DO - 10.1002/cncr.32053
M3 - Article
C2 - 31012964
AN - SCOPUS:85068394439
SN - 0008-543X
VL - 125
SP - 2409
EP - 2422
JO - Cancer
JF - Cancer
IS - 14
ER -