EphA2, a receptor tyrosine kinase, is overexpressed in various cancers. Its ligand-independent non-canonical signaling is pro-tumorigenic, and elevated EphA2 expression is associated with poor prognosis in patients. Although preclinical and clinical studies targeting EphA2 have been conducted as cancer therapeutics, its role in the DNA damage response remains elusive. This study examined the role of EphA2 in cell cycle progression in Adriamycin (ADR)-treated cells. ADR treatment transcriptionally upregulated EphA2 expression in a p53-independent manner. Suppression of EphA2 upregulation abrogated G2 arrest, as evidenced by reductions in both cyclin B1 accumulation and Wee1 inhibition-driven cell division. However, the 2N-G1 cell population remained low, with increased tetraploid cells. Time-lapse imaging revealed that tetraploid formation resulted from mitotic bypass rather than mitotic slippage or cytokinesis failure. EphA2 knockdown upregulated p21 expression together with p53, and p21 knockdown suppressed EphA2 knockdown-induced mitotic bypass. Monitoring fluorescence from a GFP fusion with the cyclin B1 destruction box demonstrated degradation in interphase without cell division, suggesting premature activation of APC/CCdh1 in interphase. Notably, p21 upregulation following EphA2 knockdown was observed specifically in cervical cancer cell lines. Finally, ADR-induced suppression of cell proliferation was further enhanced by EphA2 knockdown and partially reversed by p21 knockdown. In conclusion, EphA2 suppression induces p21-dependent mitotic bypass and tetraploidization, leading to reduced cell proliferation. EphA2 upregulation following DNA damage may be pro-tumorigenic by maintaining G2 arrest to keep DNA damage at tolerable levels. These findings provide a rationale for combining EphA2 inhibition with DNA-damaging agents in certain cancer types.
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Ayuka Nakamura
Junna Tanaka
Ryuzaburo Yuki
Journal of Biological Chemistry
Kyoto Pharmaceutical University
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Nakamura et al. (Sun,) studied this question.
www.synapsesocial.com/papers/69a7689ebadf0bb9e87e554f — DOI: https://doi.org/10.1016/j.jbc.2026.111271
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