FOXO4-DRI induces keloid senescent fibroblast apoptosis by promoting nuclear exclusion of upregulated p53-serine 15 phosphorylation

Communications Biology, Год журнала: 2025, Номер 8(1)

Опубликована: Фев. 24, 2025

Keloids are pathological scars exhibiting tumour-like aggressiveness and high recurrence rate. Here we find increased proportion of pro-inflammatory mesenchymal fibroblast subpopulations senescent fibroblasts, enhanced expression senescence-associated secretory phenotype genes using single-cell RNA sequencing analysis, as well elevated p16 protein more β-galactosidase-positive cells in keloids. The up-regulated p53-serine15 phosphorylation (p53-pS15) keloids is identified by phosphospecific microarray western blotting. We further demonstrate that a senolytic FOXO4-D-retro-inverso-isoform peptide (FOXO4-DRI) promotes apoptosis decreases G0/G1 phase pro-senescence models keloid organ cultures accompanied with p53-pS15 nuclear exclusion. Our study indicates upregulation maintains persistent microenvironment to promote cell cycle arrest resistance fibroblasts. FOXO4-DRI shows potential treatment targeting the senescence resistance, holds promise an approach prevent relapse Senolytic selectively eliminates fibroblasts inducing exclusion p53 phosphorylation, highlighting role overgrowth relapse.

Язык: Английский

---

The role of VEGF in vascular dementia: impact of aging and cellular senescence

Biogerontology, Год журнала: 2025, Номер 26(2)

Опубликована: Март 22, 2025

Язык: Английский

---

Potentiating doxorubicin activity through BCL-2 inhibition in p53 wild-type and mutated triple-negative breast cancer

Frontiers in Oncology, Год журнала: 2025, Номер 15

Опубликована: Апрель 2, 2025

Triple-negative breast cancer (TNBC) is an aggressive sub-type of that associated with higher rates recurrent disease. Chemotherapy anthracycline integral part curative therapy but resistance remains a clinical problem. Cellular senescence terminal cell fate has been observed in models doxorubicin resistance. Identifying novel combinations to eliminate senescent cells and promote apoptosis may lead improved outcomes. The purpose this study was investigate the combination pro-apoptotic BCL-2 inhibitor venetoclax TNBC lines assess role p53 cellular apoptosis. wild-type (WT), mutated or knocked-down (KD) were treated doxorubicin, vitro evaluated for impacts on viability, proliferation, apoptosis, senescence. Down-stream markers also assessed evaluate mechanistic changes. An vivo MDA-MB-231 murine model used tumor growth, changes following treatment combination. Venetoclax had synergistic antiproliferative activity against increased addition reduced p53-independent manner. In vivo, growth inhibition cells. promising p53-WT work supports further investigation.

Язык: Английский

---

A Novel ALDH1A1 Inhibitor Blocks Platinum-Induced Senescence and Stemness in Ovarian Cancer

Cancers, Год журнала: 2022, Номер 14(14), С. 3437 - 3437

Опубликована: Июль 15, 2022

Ovarian cancer is a deadly disease attributed to late-stage detection as well recurrence and the development of chemoresistance. stem cells (OCSCs) are hypothesized be largely responsible for emergence chemoresistant tumors. Although chemotherapy may initially succeed at decreasing size number tumors, it leaves behind residual malignant OCSCs. In this study, we demonstrate that aldehyde dehydrogenase 1A1 (ALDH1A1) essential survival We identified first-in-class ALDH1A1 inhibitor, compound

Язык: Английский

---

Transcriptional Heterogeneity of Cellular Senescence in Cancer

Molecules and Cells, Год журнала: 2022, Номер 45(9), С. 610 - 619

Опубликована: Авг. 19, 2022

Cellular senescence plays a paradoxical role in tumorigenesis through the expression of diverse senescence-associated (SA) secretory phenotypes (SASPs).The heterogeneity SA gene cancer cells not only promotes stemness but also protects these from chemotherapy.Despite potential correlation between and biomarkers, many transcriptional changes across distinct cell populations remain largely unknown.During past decade, single-cell RNA sequencing (scRNA-seq) technologies have emerged as powerful experimental analytical tools to dissect such senescence-derived changes.Here, we review recent efforts that successfully characterized scRNA-seq data obtained elucidated senescent tumor malignancy.We further highlight functional implications genes expressed specifically stromal microenvironment.Translational research leveraging profiling will facilitate identification novel patterns underlying susceptibility, providing new therapeutic opportunities era precision medicine.

Язык: Английский

---