Work

Targeted reactivation of the novel tumor suppressor DAPK1, an upstream regulator of p53, in high‐grade serous ovarian cancer by mRNA liposomes reduces viability and enhances drug sensitivity in preclinical models

Year: 2025

Type: article

Abstract: Targeted reactivation of the novel tumor suppressor DAPK1, an upstream regulator of p53, in high-grade serous ovarian cancer by mRNA liposomes reduces viability and enhances drug sensitivity in preclinical models Ovarian cancer, particularly high-grade serous ovarian cancer (HGSOC), remains the most lethal gynecological malignancy, with a 5-year survival rate of around 40% due to late diagnosis, recurrence, and the development of chemoresistance [1,2].Mutations in tumor protein 53 (TP53) occur in over 96% of HGSOC cases, impairing its tumor-suppressive functions, including cell cycle control, DNA repair, and apoptosis.Mutant TP53 promotes tumor progression, genomic instability, and resistance to standard therapies, thereby worsening patient outcomes [3,4].Death-associated protein kinase 1 (DAPK1) is a key regulator of apoptosis and autophagy [5,6].While p53 can upregulate DAPK1 expression, DAPK1 in turn stabilizes p53 by inhibiting its negative regulator, murine double minute 2 (MDM2).This reciprocal regulation forms a feedback loop that reinforces p53's tumor-suppressive function.We identified aberrant DAPK1 expression in ovarian can-List of abbreviations: HGSOC, high-grade serous ovarian cancer; DAPK1, death-associated protein kinase 1; TP53, tumor protein 53; IVT-mRNA, in vitro transcribed-messenger RNA; KD-AR-DD, kinase-ankyrin repeats-and death-domain; KD-AR-ROC-COR-DD, kinase-,-ankyrin repeats-, ras of complex-, C-terminal of ROC-, and death-domain; KD-AR-ROC-DD, kinase-,-ankyrin repeats-, ras of complex-and death-domain; KD-COR-DD, kinase-,-C-terminal of ROC-, and death-domain; KD-DD, kinase-and-death domain; KD, kinase domain; OVCAR-3/-4-5/-8-PTX, ovarian cancer cell lines with "PTX" indicating paclitaxel resistance.; p14ARF, alternate reading frame protein; p21 (CIP1/WAF1), cyclin-dependent kinase inhibitor p21; p16 (INK4a), cyclin-dependent kinase inhibitor that inhibits CDK4/6; Bax, Bcl-2-associated X protein; p53-pS20, p53 phospho-Serine 20; PLK1, polo-like kinase 1; Aurora A, Aurora kinase A; CDK1, cyclin-dependent kinase 1; PARP, poly (ADP-Ribose) polymerase; FAS, fas cell surface death receptor; Puma, p53 upregulated modulator of apoptosis; Noxa, pro-apoptotic protein regulated by p53; Luc, Luciferase; HUVEC, human umbilical vein endothelial cells; IVIS, in vivo imaging system; pBeclin, phospho-Beclin pThr 119; MCL2, myosin-light chain 2; MDM2, murine double minute 2.

Source: 癌症：英文版

DOI: 10.1002/cac2.70029