|Title||Activating p53 family member TAp63: A novel therapeutic strategy for targeting p53-altered tumors.|
|Publication Type||Journal Article|
|Year of Publication||2019|
|Authors||Gunaratne, PH, Pan, Y, Rao, AK, Lin, C, Hernandez-Herrera, A, Liang, K, Rait, AS, Venkatanarayan, A, Benham, AL, Rubab, F, Kim, SSoo, Rajapakshe, K, Chan, CK, Mangala, LS, Lopez-Berestein, G, Sood, AK, Rowat, AC, Coarfa, C, Pirollo, KF, Flores, ER, Chang, EH|
|Date Published||2019 Apr 23|
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.
|Grant List||1 S10 RR 15768-01 / / U.S. Public Health Service / |
RP110355 / / Cancer Prevention and Research Institute of Texas /
RP120124 / / Cancer Prevention and Research Institute of Texas /
RP150094 / / Cancer Prevention and Research Institute of Texas /
DBI-1254185 / / National Science Foundation /
HU0001 / / National Foundation for Cancer Research /
1R01 CA218025-01 / / National Cancer Institute /
1R01CA160394-01A1 / / National Cancer Institute /
2P30-CA-51008 / / National Cancer Institute /
5R01CA132012-02 / / National Cancer Institute /
5T32CA009686-19 / / National Institutes of Health /
C06RR14567 / / National Institutes of Health /
R00DK094981 / / National Institutes of Health /