P21 Overexpression Promotes Cell Death and Induces Senescence in Human Glioblastoma

Mansour, Moustafa; Rahman, Masum; Ayad, Ahmad A.; Warrington, Arthur E.; Burns, Terry C.

doi:10.3390/cancers15041279

Cited by 15 publications

(5 citation statements)

References 38 publications

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“…Conversely, elimination of the SA-β-gal-positive population by navitoclax enriched for cells expressing normal p21 levels. Elevated levels of p21 itself can induce senescence, as shown in several cell lines, including GBM (50,51). Interestingly, this induction can be prevented by restricting cellular size growth using mTOR inhibitors (50).…”

Section: Discussionmentioning

confidence: 99%

BMP4 induces a p21-dependent cell state shift in glioblastoma linking mesenchymal transition to senescence

Niklasson,

Dalmo,

Segerman

et al. 2024

Preprint

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Bone morphogenetic protein 4 (BMP4) has emerged as a potential glioblastoma therapy due to its anti- proliferative effect via SOX2 downregulation and differentiation promotion. However, BMP4 responses vary across and within tumors. Our previous data indicate that BMP4 induces transition to a mesenchymal-like cell state. Mesenchymal transition is associated with therapy-resistance and tumor recurrence, as is senescence in cancer.In this study, we investigated BMP4’s potential to induce senescence in primary glioblastoma cells, including proneural- and mesenchymal-like clones derived from the same tumor. BMP4 treatment induced senescence-associated genes and phenotypic changes such as cell enlargement, senescence- associated-β-gal expression, lamin B1 downregulation, and elevated p21 levels. The most robust senescence induction was observed in the mesenchymal-like clone, compared to its proneural counterpart. Notably, mesenchymal-like cells displayed high basal levels of p21 and other senescence- associated markers, suggesting a convergence of mesenchymal and senescent traits. p21 knockout abolished BMP4-induced senescence, maintaining proliferation and cell size despite SOX2 downregulation. Additionally, senolytic treatment effectively eliminated senescent cells through apoptosis, thereby favoring survival of cells retaining normal p21 levels.Our findings demonstrate BMP4’s ability to induce p21-dependent senescence in glioblastoma, particularly in therapy-resistant mesenchymal-like cells. These insights provide potential therapeutic strategies targeting senescence pathways in this challenging disease.

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Section: Discussionmentioning

confidence: 99%

BMP4 induces a p21-dependent cell state shift in glioblastoma linking mesenchymal transition to senescence

Niklasson,

Dalmo,

Segerman

et al. 2024

Preprint

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show abstract

“…In response to p53 transcription factor activity, p21 induction may result in tumor growth arrest through the inhibition of cyclin-dependent kinase complexes, proliferation cell nuclear antigen, transcription factors and coactivators ( 25 ). The overexpression of p21 has been demonstrated to promote cell death and induce senescence in human glioblastoma ( 27 ). Consistent with this, the present study has confirmed that p21-knockdown promotes the proliferation of GBM cells.…”

Section: Discussionmentioning

confidence: 99%

Ubiquitination of p21 by E3 ligase RNF135 promotes the proliferation of human glioblastoma cells

Gu,

Wang,

et al. 2024

Oncol Lett

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Glioblastoma multiforme (GBM) is a highly heterogeneous tumor of the central nervous system with a high mortality rate. The upregulation of RING finger protein 135 (RNF135), an E3 ligase, has been observed in GBM, but the associated mechanisms have not been fully elucidated. The aim of the present study was to identify the substrate of RNF135 and study its functions in GBM. Bioinformatics analyses were performed. In addition, RNF135 was overexpressed or knocked down in human U87 and U251 GBM cells, and the effect on cell proliferation was analyzed using Cell Counting Kit-8 and colony formation assays. Furthermore, the interaction of RNF135 with its potential substrate was analyzed using glutathione S-transferase, yeast two-hybrid, immunoprecipitation (IP), co-IP and immunoblotting assays. Bioinformatics analysis indicated that RNF135 serves as a marker of poor prognosis in GBM. The overexpression of RNF135 was demonstrated to promote the proliferation of GBM cells, while the knockdown of RNF135 inhibited GBM cell growth. In addition, the results of the interaction experiments indicate that RNF135 interacts with p21 and mediates the degradation of p21 by ubiquitination. The major site of RNF135-mediated p21 ubiquitination was identified as K163. Further experiments demonstrated that RNF135 promotes the proliferation of GBM cells mainly via p21. In summary, these findings suggest that RNF135 has potential as a therapeutic target for the treatment of GBM.

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“…Te detection of apoptosis-related proteins using a human apoptotic antibody kit showed that the expression of the apoptosis-inhibiting protein survivin and proliferationinhibiting protein p21 were diferent between A2ML1 overexpression ESCC cells and the control group. p21, a well-established cyclin-dependent kinase inhibitor, plays an important role in controlling cell-cycle progression [20,21]. Moreover, p21 is mainly associated with p53 during cell-cycle arrest.…”

Section: Discussionmentioning

confidence: 99%

A2ML1 Inhibits Esophageal Squamous Cell Carcinoma Progression and Serves as a Novel Prognostic Biomarker

Zhang,

Tang,

Lian

et al. 2023

Canadian Journal of Gastroenterology and Hepatology

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Studies have established a correlation between α2-macroglobulin-like 1 (A2ML1) and the prognosis of lung, pancreatic, and breast cancers; however, research on its involvement in the pathogenesis of esophageal carcinoma remains limited. Therefore, in this study, we aimed to investigate the role of A2ML1 in the progression of esophageal squamous cell carcinoma (ESCC). Immunohistochemical staining was employed to assess the expression level of A2ML1 protein in both tumor and adjacent normal tissues of patients with ESCC. The Kaplan–Meier method, along with univariate and multivariate Cox risk ratio analyses, was used to determine survival rates and prognostic factors. Furthermore, two human ESCC cell lines, KYSE30 and KYSE150, were used to assess the effect of A2ML1 overexpression on cell proliferation and apoptosis. A human apoptosis antibody kit was also used to analyze the downstream action proteins of A2ML1, and a nude mouse xenotransplantation model was used to evaluate the effect of A2ML1 on ESCC tumorigenesis in vivo. The protein level of A2ML1 in ESCC tissues was significantly lower than that in normal esophageal tissues, and higher A2ML1 protein levels were associated with smaller ESCC tumor sizes and improved tumor-specific survival rates. Multivariate analysis established A2ML1 as a novel independent prognostic factor for ESCC. Moreover, A2ML1 overexpression significantly inhibited ESCC cell proliferation and promoted apoptosis. A2ML1 consistently inhibited tumor growth in mouse models. Furthermore, the human apoptotic antibody kit results showed increased expression of the proliferation-inhibiting protein p21 downstream of KYSE150 cells overexpressing A2ML1. Our findings demonstrate that a correlation exists between A2ML1 and ESCC prognosis and that A2ML1 plays an antitumor role in ESCC progression. This study underscores the potential of A2ML1 as a novel biomarker for predicting the prognosis of ESCC.

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P21 Overexpression Promotes Cell Death and Induces Senescence in Human Glioblastoma

Cited by 15 publications

References 38 publications

BMP4 induces a p21-dependent cell state shift in glioblastoma linking mesenchymal transition to senescence

BMP4 induces a p21-dependent cell state shift in glioblastoma linking mesenchymal transition to senescence

Ubiquitination of p21 by E3 ligase RNF135 promotes the proliferation of human glioblastoma cells

A2ML1 Inhibits Esophageal Squamous Cell Carcinoma Progression and Serves as a Novel Prognostic Biomarker

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