FOXO1 Inhibition and FADD Knockdown Have Opposing Effects on Anticancer Drug-Induced Cytotoxicity and p21 Expression in Osteosarcoma Cells

Authors

Danielle Walker
Antanay Hall
Alexis Bonwell
Nancy Gordon
Danielle Robinson
Mario G Hollomon

Language

English

Publication Date

1-17-2026

Journal

International Journal of Molecular Sciences

DOI

10.3390/ijms27020935

PMID

41596582

PMCID

PMC12842461

PubMedCentral® Posted Date

1-17-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Forkhead box class O1 (FOXO1) and fas-associated death domain (FADD) regulate cell death pathways and homeostatic processes such as cell cycle progression and apoptosis. FADD phosphorylation promotes nuclear localization of FOXO1, and FOXO1 regulates FADD expression. Therefore, it is plausible that FOXO1 and FADD have synergistic or antagonistic effects on cell cycle regulation and the response to anticancer drug treatment in cancer cells. In the present study, we report that AS1842856-mediated inhibition of FOXO1 reverses anticancer drug-induced cytotoxicity, while FADD knockdown increases anticancer drug-induced cytotoxicity in osteosarcoma (OS). Reversed anticancer drug-induced cytotoxicity was accompanied by G2/M cell cycle arrest and increased expression of p21. The anticancer function of FOXO1 was further supported by the observation that OS cells that express higher basal levels of FOXO1 had increased sensitivity to camptothecin-induced cytotoxicity. FADD knockdown reversed the FOXO1 inhibition-induced increase in p21 expression. The results presented in this study indicate that FOXO1 has a tumor suppressor function, while FADD has a tumor-promoting function in OS following anticancer drug treatment. The experimental approach used in this investigation also indicates that FADD antagonizes the effect of FOXO1 on p21 expression in OS.

Keywords

Forkhead Box Protein O1, Humans, Osteosarcoma, Fas-Associated Death Domain Protein, Cyclin-Dependent Kinase Inhibitor p21, Cell Line, Tumor, Antineoplastic Agents, Gene Knockdown Techniques, Gene Expression Regulation, Neoplastic, Apoptosis, Bone Neoplasms, FOXO1, FADD, cell cycle, osteosarcoma

Published Open-Access

yes

Recommended Citation

Walker, Danielle; Hall, Antanay; Bonwell, Alexis; et al., "FOXO1 Inhibition and FADD Knockdown Have Opposing Effects on Anticancer Drug-Induced Cytotoxicity and p21 Expression in Osteosarcoma Cells" (2026). Faculty, Staff and Student Publications. 5761.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5761