Biology subjects

Ochiiwa, H.

Publications and source records attributed to Ochiiwa, H..

3 recordsLinked to original sources

bioRxiv2026

Temporal regulation of G2 phase avoids therapy-induced senescence caused by DNA replication stress-inducing drugs and provides synergistic cytotoxicity

The cellular response to DNA replication stress (DRS) provoked by anticancer drugs involves activation of the G2/M checkpoint (which promotes transient cell cycle arrest at G2 phase) and DNA repair, followed by induction of apoptosis or senescence. Here, we activated the p53-p21 pathway and ATR using DRS-inducing drugs, and found that that the transition to senescence depends on the duration of the G2 phase. Shortening of G2 duration by G2/M checkpoint inhibitors led not only to a switch in cell fate from senescence to mitotic entry, but also to effective cell death through carry-over of chromosomal aberrations (generated by DRS-inducing drugs) into mitosis and subsequent mitotic progression. Such enhanced cell death was also observed in p53 deficient cells, which do not normally undergo senescence. Thus, we propose that temporal regulation of G2 phase is an approach to enhancing the effects of DRS-inducing drugs in a manner that is independent of p53 status.

cell biology↗

bioRxiv2025

IAP antagonists potentiate TNFα-triggered apoptosis but selectively eliminate senescent tumor cells independently of TNFα

Therapy-induced senescence (TIS) is a state of cell division arrest induced by chemotherapy that blocks tumor growth. TIS tumor cells affect the tumor microenvironment through their senescence-associated secretory phenotype and independently acquire stemness, which makes them more aggressive and causes relapse once they regrow. To eradicate tumors by chemotherapy, long-lived TIS tumor cells must be efficiently eliminated. Here, we show that AZD5582 and AT406, which are potent antagonists of inhibitor of apoptosis proteins (IAP antagonists) that suppress the activities of cellular inhibitor of apoptosis protein 1 (cIAP1), cellular inhibitor of apoptosis protein 2 (cIAP2), and X-linked inhibitor of apoptosis protein (XIAP), selectively induced apoptosis mediated by caspase 8 and effector caspases in TIS tumor cells, which produced and secreted tumor necrosis factor (TNF). However, these IAP antagonists were still selectively cytotoxic to TIS tumor cells even when TNF was absent (TNF-knockout cells) or neutralized (by a neutralizing antibody), indicating they have TNF-independent senolytic activity. Consistently, these IAP antagonists also sensitized tumor cells that had been induced to become senescent by nutlin-3a, which activates p53 but does not trigger TNF production. Furthermore, TNF sensitized tumor cells treated with these IAP antagonists irrespective of their senescence status. Collectively, these data indicate that IAP antagonists that inhibit cIAPs and XIAP not only potentiate TNF-triggered apoptosis but also have TNF-independent senolytic activity. We propose that IAP antagonists are good concomitant drugs of chemotherapy that induces TIS, not only as senolytic drugs but also as sensitizers of adjacent non-senescent tumor cells mediated by paracrine TNF.

cancer biology↗

bioRxiv2023

The anti-tumor effect of trifluridine via induction of aberrant mitosis is unaffected by mutations modulating p53 activity

The fluorinated thymidine analogue trifluridine (FTD) is a chemotherapeutic drug commonly used to treat cancer; however, the mechanism by which FTD induces cytotoxicity is not fully understood. In addition, the effect of gain-of-function (GOF) missense mutations of the TP53 gene (encoding p53), which promote cancer progression and chemotherapeutic drug resistance, on the chemotherapeutic efficacy of FTD is unclear. Here, we revealed the mechanisms by which FTD induced aberrant mitosis and contributed to cytotoxicity in both p53-null and p53-GOF missense mutant cells. In p53-null mutant cells, FTD induced DNA double-stranded breaks, single-stranded DNA accumulation, and the associated DNA damage repair responses during G2 phase. Nevertheless, FTD-induced DNA damage and the related responses were not sufficient to trigger strict G2/M checkpoint arrest. Thus, these features were carried over into mitosis, resulting in chromosome breaks and bridges, and subsequent cytokinesis failure. Improper mitotic exit eventually led to cell apoptosis, caused by the accumulation of extensive DNA damage and the presence of micronuclei encapsulated in the disrupted nuclear envelope. Upon FTD treatment, the behavior of the p53-GOF-missense-mutant, isogenic cell lines, generated by CRISPR/Cas9 genome editing, was similar to that of p53-null mutant cells. Thus, our data suggest that FTD treatment overrode the effect on gene expression induced by p53-GOF mutants and exerted its anti-tumor activity in a manner that was independent of p53 function.

cell biology↗