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Highly concentrated trehalose induces prohealing senescence-like state in fibroblasts via CDKN1A/p21.

ABSTRACT: Trehalose is the nonreducing disaccharide of glucose, evolutionarily conserved in invertebrates. The living skin equivalent (LSE) is an organotypic coculture containing keratinocytes cultivated on fibroblast-populated dermal substitutes. We demonstrated that human primary fibroblasts treated with highly concentrated trehalose promote significantly extensive spread of the epidermal layer of LSE without any deleterious effects. The RNA-seq analysis of trehalose-treated 2D and 3D fibroblasts at early time points revealed the involvement of the CDKN1A pathway, the knockdown of which significantly suppressed the upregulation of DPT, ANGPT2, VEGFA, EREG, and FGF2. The trehalose-treated fibroblasts were positive for senescence-associated β-galactosidase. Finally, transplantation of the dermal substitute with trehalose-treated fibroblasts accelerated wound closure and increased capillary formation significantly in the experimental mouse wounds in vivo, which was canceled by the CDKN1A knockdown. These data indicate that high-concentration trehalose can induce the senescence-like state in fibroblasts via CDKN1A/p21, which may be therapeutically useful for optimal wound repair.

SUBMITTER: Muto J

PROVIDER: S-EPMC9822918 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Highly concentrated trehalose induces prohealing senescence-like state in fibroblasts via CDKN1A/p21.

Muto Jun J Fukuda Shinji S Watanabe Kenji K Dai Xiuju X Tsuda Teruko T Kiyoi Takeshi T Kameda Kenji K Kawakami Ryosuke R Mori Hideki H Shiraishi Ken K Murakami Masamoto M Imamura Takeshi T Higashiyama Shigeki S Fujisawa Yasuhiro Y Mizukami Yoichi Y Sayama Koji K

Communications biology 20230106 1

Trehalose is the nonreducing disaccharide of glucose, evolutionarily conserved in invertebrates. The living skin equivalent (LSE) is an organotypic coculture containing keratinocytes cultivated on fibroblast-populated dermal substitutes. We demonstrated that human primary fibroblasts treated with highly concentrated trehalose promote significantly extensive spread of the epidermal layer of LSE without any deleterious effects. The RNA-seq analysis of trehalose-treated 2D and 3D fibroblasts at ear ...[more]

PMID: 36609486

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Project description:Deletion and mutation of phosphatase and tensin homolog deleted on chromosome10 (PTEN) are closely associated with the occurrence of tumors. Tumor suppressor gene PTEN mutation plays an important role in the pathogenesis of ovarian cancer. However, it has been unclear whether it can regulate the senescence of ovarian cancer cells. We speculated that PTEN might inhibit the occurrence and development of ovarian cancer by promoting the expression of P21. We found that the expression of TRIM39 in human ovarian cancer was significantly diminished. In SKOV3 cells treated with naringin, the expression of TRIM39, which binds P21 and inhibits P21 degradation, was significantly elevated. Real-time polymerase chain reaction (PCR), Western blot, and immunofluorescence were used to detected the expression of PTEN, p21, and TRIM39, β-galactosidase Staining was used to detect cell senescence, Ki67 staining was used to observe cell proliferation, Trim39 interference or overexpression assay was used to detect its function. We speculated that PTEN might promote SKOV3 cell senescence by increasing TRIM39 expression and decreasing P21 degradation. Furthermore, by interfering with TRIM39 in SKOV3 cells, we found that the expression of P21 was downregulated, and the number of senescent SKOV3 cells decreased. With overexpression of TRIM39 in SKOV3 cells, the expression of P21 was upregulated, and the number of senescent SKOV3 cells increased. When naringin, a PTEN agonist, was added to SKOV3 cells in which TRIM39 protein was interfered with, the expression of P21 was significantly lower than that in the control group, and the number of senescent ovarian cancer cells was significantly diminished. Our results indicated that PTEN maintained the stability of P21 and decreased the degradation of P21 by increasing TRIM39 expression, thus promoting the senescence of SKOV3 cells, and PTEN maintained the stability of p21 and promoted the aging of SKOV3 cells might be a novel therapeutic target for ovarian cancer.

Project description:Simple Summary Current standard care for high-grade glioma involves maximal safe resection followed by chemoradiation. Recent studies showed that surviving cancer cells with an initially senescent phenotype following chemoradiation could escape senescence over time, giving rise to tumor cells that were more aggressive and resilient. Therefore, more powerful approaches are needed to either keep these glioma-initiating cells in a senescent state for longer or to eliminate these senescent cells prior to tumor recurrence. In this study, we demonstrate that P21 overexpression induces high levels of apoptosis in multiple human glioma cell lines and, in surviving cells, promotes cell cycle arrest and senescent gene expression. Additionally, we demonstrate that P21 overexpression induces senescence more rapidly and stably than the irradiation of human glioblastoma cells. Finally, we find that P21-overexpressing glioma cells selectively depend upon Bcl-xL to avoid apoptotic cell death. Abstract High-grade gliomas are the most common and aggressive adult primary brain tumors with a median survival of only 12–15 months. Current standard therapy consists of maximal safe surgical resection followed by DNA-damaging agents, such as irradiation and chemotherapy that can delay but not prevent inevitable recurrence. Some have interpreted glioma recurrence as evidence of glioma stem cells which persist in a relatively quiescent state after irradiation and chemotherapy, before the ultimate cell cycle re-entry and glioma recurrence. Conversely, latent cancer cells with a therapy-induced senescent phenotype have been shown to escape senescence, giving rise to more aggressive stem-like tumor cells than those present in the original tumor. Therefore, approaches are needed to either eliminate or keep these glioma initiating cells in a senescent state for a longer time to prolong survival. In our current study, we demonstrate that the radiation-induced cell cycle inhibitor P21 can provide a powerful route to induce cell death in short-term explants of PDXs derived from three molecularly diverse human gliomas. Additionally, cells not killed by P21 overexpression were maintained in a stable senescent state for longer than control cells. Collectively, these data suggest that P21 activation may provide an attractive therapeutic target to improve therapeutic outcomes.

Dataset Information

Highly concentrated trehalose induces prohealing senescence-like state in fibroblasts via CDKN1A/p21.

Publications

Highly concentrated trehalose induces prohealing senescence-like state in fibroblasts via CDKN1A/p21.

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