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

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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.

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