Cellular senescence signaling in cancer: A novel therapeutic target to combat human malignancies

Fakhri, Sajad; Moradi, Seyed Zachariah; DeLiberto, Lindsay K.; Bishayee, Anupam

doi:10.1016/j.bcp.2022.114989

Cited by 13 publications

(6 citation statements)

References 311 publications

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“…5 D, a noticeable shift in gene expression patterns within the networks becomes apparent after the pre-deterioration state, where gene expression levels demonstrate distinct changes, transitioning from either high to low or the reverse. Figure 5 E reveals that these neighboring differentially expressed genes (DEGs) exhibited significant enrichment in cancer-related signaling pathways, including the phosphatidylinositol 3-kinase (PI3K)–Akt signaling pathway [ 27 ], cellular senescence [ 28 ], and the FoxO signaling pathway [ 29 ].…”

Section: Resultsmentioning

confidence: 99%

Uncovering the Pre-Deterioration State during Disease Progression Based on Sample-Specific Causality Network Entropy (SCNE)

Zhong,

Tang,

Huang

et al. 2024

Research

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Complex diseases do not always follow gradual progressions. Instead, they may experience sudden shifts known as critical states or tipping points, where a marked qualitative change occurs. Detecting such a pivotal transition or pre-deterioration state holds paramount importance due to its association with severe disease deterioration. Nevertheless, the task of pinpointing the pre-deterioration state for complex diseases remains an obstacle, especially in scenarios involving high-dimensional data with limited samples, where conventional statistical methods frequently prove inadequate. In this study, we introduce an innovative quantitative approach termed sample-specific causality network entropy (SCNE), which infers a sample-specific causality network for each individual and effectively quantifies the dynamic alterations in causal relations among molecules, thereby capturing critical points or pre-deterioration states of complex diseases. We substantiated the accuracy and efficacy of our approach via numerical simulations and by examining various real-world datasets, including single-cell data of epithelial cell deterioration (EPCD) in colorectal cancer, influenza infection data, and three different tumor cases from The Cancer Genome Atlas (TCGA) repositories. Compared to other existing six single-sample methods, our proposed approach exhibits superior performance in identifying critical signals or pre-deterioration states. Additionally, the efficacy of computational findings is underscored by analyzing the functionality of signaling biomarkers.

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Section: Resultsmentioning

confidence: 99%

Uncovering the Pre-Deterioration State during Disease Progression Based on Sample-Specific Causality Network Entropy (SCNE)

Zhong,

Tang,

Huang

et al. 2024

Research

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“…Then, by exploring the impact of 39 cell senescence-associated genes on the overall survival of GBM patients, we identified 11 cell senescence-associated genes with statistically significant effects on the survival and prognosis of GBM patients (P < 0.005), which included PTTG1 and MYC. Currently, enormous shreds of evidence reveal that CS is an effective anti-tumor mechanism and proto oncogene-induced cell senescence is a barrier to preventing tumorigenesis as well as a target to treat tumors [ 46 , 47 ]. PTTG1 in normal human fibroblasts can inhibit cell proliferation and result in several cell senescence-related events, including increasing SA-beta-galactosidase activity and SA-heterochromatin foci formation, decreasing BrdU incorporation [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

Cell senescence-associated genes predict the malignant characteristics of glioblastoma

et al. 2022

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Background Glioblastoma (GBM) is the most malignant, aggressive and recurrent primary brain tumor. Cell senescence can cause irreversible cessation of cell division in normally proliferating cells. According to studies, senescence is a primary anti-tumor mechanism that may be seen in a variety of tumor types. It halts the growth and spread of tumors. Tumor suppressive functions held by cellular senescence provide new directions and pathways to promote cancer therapy. Methods We comprehensively analyzed the cell senescence-associated genes expression patterns. The potential molecular subtypes were acquired based on unsupervised cluster analysis. The tumor immune microenvironment (TME) variations, immune cell infiltration, and stemness index between 3 subtypes were analyzed. To identify genes linked with GBM prognosis and build a risk score model, we used weighted gene co-expression network analysis (WGCNA), univariate Cox regression, Least absolute shrinkage and selection operator regression (LASSO), and multivariate Cox regression analysis. And the correlation between risk scores and clinical traits, TME, GBM subtypes, as well as immunotherapy responses were estimated. Immunohistochemistry (IHC) and cellular experiments were performed to evaluate the expression and function of representative genes. Then the 2 risk scoring models were constructed based on the same method of calculation whose samples were acquired from the CGGA dataset and TCGA datasets to verify the rationality and the reliability of the risk scoring model. Finally, we conducted a pan-cancer analysis of the risk score, assessed drug sensitivity based on risk scores, and analyzed the pathways of sensitive drug action. Results The 3 potential molecular subtypes were acquired based on cell senescence-associated genes expression. The Log-rank test showed the difference in GBM patient survival between 3 potential molecular subtypes (P = 0.0027). Then, 11 cell senescence-associated genes were obtained to construct a risk-scoring model, which was systematically randomized to distinguish the train set (n = 293) and the test set (n = 292). The Kaplan-Meier (K-M) analyses indicated that the high-risk score in the train set (P < 0.0001), as well as the test set (P = 0.0053), corresponded with poorer survival. In addition, the high-risk score group showed a poor response to immunotherapy. The reliability and credibility of the risk scoring model were confirmed according to the CGGA dataset, TCGA datasets, and Pan-cancer analysis. According to drug sensitivity analysis, it was discovered that LJI308, a potent selective inhibitor of RSK pathways, has the highest drug sensitivity. Moreover, the GBM patients with higher risk scores may potentially be more beneficial from drugs that target cell cycle, mitosis, microtubule, DNA replication and apoptosis regulation signaling. Conclusion We identified potential associations between clinical characteristics, TME, stemness, subtypes, and immunotherapy, and we clarified the therapeutic usefulness of cell senescence-associated genes.

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“…Recent studies demonstrated MAPK-signaling cascade and its main subfamilies, such as extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p38 plays pivotal roles in inflammation/oxidative stress-associated angiogenesis. Besides phosphatases and tensin homolog (PTEN)/PI3K/Akt/mTOR, Janus kinase (JAK)/STAT and Ras/Raf/mitogen-activated protein kinase (MEK)/ERK/MAPK signaling pathways are also interconnected with the modulation of inflammation, oxidative stress, and cancer cells survival [ 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. Oxidative stress is another trigger of angiogenesis that linked with aforementioned signaling pathways.…”

Section: Angiogenesis: Cellular Signaling Pathwaysmentioning

confidence: 99%

Inhibiting Angiogenesis by Anti-Cancer Saponins: From Phytochemistry to Cellular Signaling Pathways

et al. 2023

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Saponins are one of the broadest classes of high-molecular-weight natural compounds, consisting mainly of a non-polar moiety with 27 to 30 carbons and a polar moiety containing sugars attached to the sapogenin structure. Saponins are found in more than 100 plant families as well as found in marine organisms. Saponins have several therapeutic effects, including their administration in the treatment of various cancers. These compounds also reveal noteworthy anti-angiogenesis effects as one of the critical strategies for inhibiting cancer growth and metastasis. In this study, a comprehensive review is performed on electronic databases, including PubMed, Scopus, ScienceDirect, and ProQuest. Accordingly, the structural characteristics of triterpenoid/steroid saponins and their anti-cancer effects were highlighted, focusing on their anti-angiogenic effects and related mechanisms. Consequently, the anti-angiogenic effects of saponins, inhibiting the expression of genes related to vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1-α (HIF-1α) are two main anti-angiogenic mechanisms of triterpenoid and steroidal saponins. The inhibition of inflammatory signaling pathways that stimulate angiogenesis, such as pro-inflammatory cytokines, mitogen-activated protein kinase (MAPKs), and phosphoinositide 3-kinases/protein kinase B (PI3K/Akt), are other anti-angiogenic mechanisms of saponins. Furthermore, the anti-angiogenic and anti-cancer activity of saponins was closely related to the binding site of the sugar moiety, the type and number of their monosaccharide units, as well as the presence of some functional groups in their aglycone structure. Therefore, saponins are suitable candidates for cancer treatment by inhibiting angiogenesis, for which extensive pre-clinical and comprehensive clinical trial studies are recommended.

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Cellular senescence signaling in cancer: A novel therapeutic target to combat human malignancies

Cited by 13 publications

References 311 publications

Uncovering the Pre-Deterioration State during Disease Progression Based on Sample-Specific Causality Network Entropy (SCNE)

Uncovering the Pre-Deterioration State during Disease Progression Based on Sample-Specific Causality Network Entropy (SCNE)

Cell senescence-associated genes predict the malignant characteristics of glioblastoma

Inhibiting Angiogenesis by Anti-Cancer Saponins: From Phytochemistry to Cellular Signaling Pathways

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