The role of oxidative stress in intervertebral disc cellular senescence

Cheng, Fengqi; Yang, Honghao; Cheng, Yunzhong; Liu, Yuzeng; Hai, Yong; Zhang, Yangpu

doi:10.3389/fendo.2022.1038171

Cited by 8 publications

(5 citation statements)

References 149 publications

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“…High concentrations of ROS induce damage to the structure of DNA and trigger DNA damage response, or directly regulate signaling pathways related to cell senescence, promoting its occurrence. [28,29] Herein, the facilitating effect of Pazopanib on the cellular senescence of ACHN cells was accompanied by an activation of OS and DNA damage, in line with the influence of resveratrol on the cell senescence of lung cancer cells reported by Liang, [28] implying that Pazopanib induced the cellular senescence in RCC cells by triggering the OS and DNA damage.…”

Section: The Effects Of Pazopanib In the Expression Of P53 And Pai In...supporting

confidence: 75%

Pazopanib stimulates senescence of renal carcinoma cells through targeting nuclear factor E2‐related factor 2 (Nrf2)

Wang,

Yang,

et al. 2024

J Biochem & Molecular Tox

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Renal cell carcinoma (RCC) is the most common kidney cancer with high mortality rate. Pazopanib has been approved for the treatment of RCC. However, the underlying mechanism is not clear. Here, we report a novel finding by showing that treatment with Pazopanib could promote cellular senescence of the human RCC cell line ACHN. Cells were stimulated with 5, 10, and 20 μM Pazopanib, respectively. Cellular senescence was measured using senescence‐associated β‐galactosidase (SA‐β‐Gal) staining. Western blot analysis and real‐time polymerase chain reaction were used to measure the mRNA and protein expression of nuclear factor E2‐related factor 2 (Nrf2), γH2AX, human telomerase reverse transcriptase (hTERT), telomeric repeat binding factor 2 (TERF2), p53 and plasminogen activator inhibitor (PAI). First, we found that exposure to Pazopanib reduced the cell viability of ACHN cells. Additionally, Pazopanib induced oxidative stress by increasing the production of reactive oxygen species, reducing the levels of glutathione peroxidase, and promoting nuclear translocation of Nrf2. Interestingly, Pazopanib exposure resulted in DNA damage by increasing the expression of γH2AX. Importantly, Pazopanib increased cellular senescence and reduced telomerase activity. Pazopanib also reduced the gene expression of hTERT but increased the gene expression of TERF2. Correspondingly, we found that Pazopanib increased the expression of p53 and PAI at both the mRNA and protein levels. To elucidate the underlying mechanism, the expression of Nrf2 was knocked down by transduction with Ad‐ Nrf2 shRNA. Results indicate that silencing of Nrf2 in ACHN cells abolished the effects of Pazopanib in stimulating cellular senescence and reducing telomerase activity. Consistently, knockdown of Nrf2 restored the expression of p53 and PAI in ACHN cells. Based on these results, we explored a novel mechanism whereby which Pazopanib displays a cytotoxicity effect in RCC cells through promoting cellular senescence mediated by Nrf2.

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Section: The Effects Of Pazopanib In the Expression Of P53 And Pai In...supporting

confidence: 75%

Pazopanib stimulates senescence of renal carcinoma cells through targeting nuclear factor E2‐related factor 2 (Nrf2)

Wang,

Yang,

et al. 2024

J Biochem & Molecular Tox

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“…Additionally, the staining of DCFH-DA revealed that knockdown of NBR1 significantly elevated the intracellular level of ROS, while the overexpression of NBR1 had the opposite effect (Figures 2 I, J and Extended Figures S2 E, F). Cell cycle arrest, elevated ECM catabolism and intracellular ROS level are hallmarks of cellular senescence 25 . Therefore, we wondered whether NBR1 inhibits intervertebral disc degeneration by retarding cellular senescence of NPCs.…”

Section: Resultsmentioning

confidence: 99%

Selective Autophagy Receptor NBR1 Retards Nucleus Pulposus Cell Senescence by Directing the Clearance of SRBD1

Song,

Zhu,

et al. 2024

Int. J. Biol. Sci.

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Intervertebral disc degeneration (IDD) is a prevalent degenerative disorder that closely linked to aging. Numerous studies have indicated the crucial involvement of autophagy in the development of IDD. However, the non-selective nature of autophagy substrates poses great limitations on the application of autophagy-related medications. This study aims to enhance our comprehension of autophagy in the development of IDD and investigate a novel therapeutic approach from the perspective of selective autophagy receptor NBR1. Proteomics and immunoprecipitation and mass spectrometry analysis, combined with in vivo and in vitro experimental verification were performed. NBR1 is found to be reduced in IDD, and NBR1 retards cellular senescence and senescence-associated secretory phenotype (SASP) of nucleus pulposus cells (NPCs), primarily through its autophagy-dependent function. Mechanistically, NBR1 knockdown leads to the accumulation of S1 RNA-binding domain-containing protein 1 (SRBD1), which triggers cellular senescence via AKT1/p53 and RB/p16 pathways, and promotes SASP via NF-κβ pathway in NPCs. Our findings reveal the function and mechanism of selective autophagy receptor NBR1 in regulating NPCs senescence and degeneration. Targeting NBR1 to facilitate the clearance of detrimental substances holds the potential to provide novel insights for IDD treatment.

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“…Aged and degenerated IVDs have increased oxidative stress and damage, possibly due to the decreased ability to repair damage [ 36 ]. The ROS contributes to DNA damage to induce CS, and molecular signaling modulation related to ROS can be targeted to control IVD senescence and degeneration [ 37 , 38 ]. Nucleus pulposus cell senescence is associated with increased ROS in IDD [ 39 ].…”

Section: Disc Cell Senescence Under Various Stressorsmentioning

confidence: 99%

Cellular Senescence in Intervertebral Disc Aging and Degeneration: Molecular Mechanisms and Potential Therapeutic Opportunities

et al. 2023

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Closely associated with aging and age-related disorders, cellular senescence (CS) is the inability of cells to proliferate due to accumulated unrepaired cellular damage and irreversible cell cycle arrest. Senescent cells are characterized by their senescence-associated secretory phenotype that overproduces inflammatory and catabolic factors that hamper normal tissue homeostasis. Chronic accumulation of senescent cells is thought to be associated with intervertebral disc degeneration (IDD) in an aging population. This IDD is one of the largest age-dependent chronic disorders, often associated with neurological dysfunctions such as, low back pain, radiculopathy, and myelopathy. Senescent cells (SnCs) increase in number in the aged, degenerated discs, and have a causative role in driving age-related IDD. This review summarizes current evidence supporting the role of CS on onset and progression of age-related IDD. The discussion includes molecular pathways involved in CS such as p53-p21CIP1, p16INK4a, NF-κB, and MAPK, and the potential therapeutic value of targeting these pathways. We propose several mechanisms of CS in IDD including mechanical stress, oxidative stress, genotoxic stress, nutritional deprivation, and inflammatory stress. There are still large knowledge gaps in disc CS research, an understanding of which will provide opportunities to develop therapeutic interventions to treat age-related IDD.

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The role of oxidative stress in intervertebral disc cellular senescence

Cited by 8 publications

References 149 publications

Pazopanib stimulates senescence of renal carcinoma cells through targeting nuclear factor E2‐related factor 2 (Nrf2)

Pazopanib stimulates senescence of renal carcinoma cells through targeting nuclear factor E2‐related factor 2 (Nrf2)

Selective Autophagy Receptor NBR1 Retards Nucleus Pulposus Cell Senescence by Directing the Clearance of SRBD1

Cellular Senescence in Intervertebral Disc Aging and Degeneration: Molecular Mechanisms and Potential Therapeutic Opportunities

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