Biomolecular bases of the senescence process and cancer. A new approach to oncological treatment linked to ageing

Badiola, Iker; Santaolalla, Francisco; García-Gallastegui, Patricia; Rey, Ana Sánchez del; Unda, Fernando; Ibarretxe, Gaskon

doi:10.1016/j.arr.2015.03.004

Cited by 21 publications

(15 citation statements)

References 212 publications

(208 reference statements)

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“…Cellular senescence is one of the important tumor-suppressive barriers. 30 , 31 , 32 , 43 It inhibits tumor cell proliferation and suppresses tumor cell motility, indicating that the induction of senescence results in the suppression of tumor cell growth, invasion and metastasis. Moreover, TRA2β4 knockdown could facilitate cellular senescence even in p53-deficient cells.…”

Section: Discussionmentioning

confidence: 99%

Ultraconserved region-containing Transformer 2β4 controls senescence of colon cancer cells

et al. 2016

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Ultraconserved regions (UCRs) are >200 bp genomic segments with perfect human-to-rodent sequence identity. Transcribed UCRs constitute a new category of noncoding RNAs whose functions remain poorly understood. The human transformer 2β (TRA2B) gene contains a 419-bp UCR spanning the 276-bp exon 2 and its neighboring introns. TRA2B exon 2 has premature stop codons, whereas an exon 2-containing splice variant (TRA2β4) was expressed preferentially in the nuclei of human colon cancer cells. TRA2β4 knockdown p53-independently stimulated CDKN1A transcription and increased p21, resulting in the appearance of senescent cells. Biotin pull-down and RNA immunoprecipitation assays revealed that TRA2β4 interacted with Sp1 through a Sp1-binding sequence (485-GGGG-488) in a stem-loop structure of exon 2. Mutation of this sequence (485-AAGG-488) disrupted the stem-loop structure, blocked the interaction with Sp1 and increased CDKN1A transcription. Overexpression of TRA2β4 significantly decreased CDKN1A mRNA levels and accelerated cell growth, but the introduction of the mutation in the Sp1-binding sequence completely canceled these effects. Taken together, TRA2β4 may sequester Sp1 from occupying promoters of target genes including CDKN1A, promoting cell growth by interrupting the senescence-related gene expression program. This novel function of TRA2β4 may uncover an oncogenic function of transcribed UCRs.

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Section: Discussionmentioning

confidence: 99%

Ultraconserved region-containing Transformer 2β4 controls senescence of colon cancer cells

et al. 2016

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“…ROS may modulate tumor suppression process, which is induced by the senescence, thus participating in anticancer mechanisms, although ROS may act as tumor promoters in definite conditions [ 48 ]. With the cell senescence and aging controlled by cells and cellular environment, the possibility is suggested that the two processes may be subjected to interventional therapies [ 203 , 204 ].…”

Section: Ros In Cell Senescencementioning

confidence: 99%

“…It is unclear if the modifications of miRNA profiles are mostly involved in pathological changes onset or if they mark the senescence end, which leads to the organ aging and dysfunction. Altered expression in miRNA activity has been observed in elderly people, as in the case of miR-34a, which belongs to a family with conserved functions in controlling aging and age-related diseases [ 203 , 231 , 232 ]. miR-34a targets ROS scavenger enzymes inducing OS [ 159 ].…”

Section: Ros In Cell Senescencementioning

confidence: 99%

“…In addition, ROS increase highly correlates with a specific miRNA dysregulation, which mediates the cross talk between p53, NF- κ B p65, and ROS. All these events have been associated with cell senescence [ 203 , 231 , 232 ]. At the same time, certainly several miRNAs families are modulated by ROS in the development of mitochondria-mediated cell senescence, which are, indirectly or directly, implicated in human pathologies [ 159 , 233 , 236 ].…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

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ROS, Cell Senescence, and Novel Molecular Mechanisms in Aging and Age‐Related Diseases

Davalli

Mitić

Caporali

et al. 2016

Oxidative Medicine and Cellular Longevity

808

579

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The aging process worsens the human body functions at multiple levels, thus causing its gradual decrease to resist stress, damage, and disease. Besides changes in gene expression and metabolic control, the aging rate has been associated with the production of high levels of Reactive Oxygen Species (ROS) and/or Reactive Nitrosative Species (RNS). Specific increases of ROS level have been demonstrated as potentially critical for induction and maintenance of cell senescence process. Causal connection between ROS, aging, age-related pathologies, and cell senescence is studied intensely. Senescent cells have been proposed as a target for interventions to delay the aging and its related diseases or to improve the diseases treatment. Therapeutic interventions towards senescent cells might allow restoring the health and curing the diseases that share basal processes, rather than curing each disease in separate and symptomatic way. Here, we review observations on ROS ability of inducing cell senescence through novel mechanisms that underpin aging processes. Particular emphasis is addressed to the novel mechanisms of ROS involvement in epigenetic regulation of cell senescence and aging, with the aim to individuate specific pathways, which might promote healthy lifespan and improve aging.

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“…Cellular senescence has recently been recognized to be an important therapeutic strategy in various types of cancer. [35][36][37] The implementation of pro-senescence strategies is therefore an attractive alternative in cancer research in terms of its chemopreventive and therapeutic potential. 38,39 Considering the function of ATG in the induction of cell senescence, a better comprehension of the underlying mechanisms is required.…”

Section: Discussionmentioning

confidence: 99%

Arctigenin induced gallbladder cancer senescence through modulating epidermal growth factor receptor pathway

et al. 2017

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Gallbladder cancer has poor prognosis and limited therapeutic options. Arctigenin, a representative dibenzylbutyrolactone lignan, occurs in a variety of plants. However, the molecular mechanisms involved in the antitumor effect of arctigenin on gallbladder cancer have not been fully elucidated. The expression levels of epidermal growth factor receptor were examined in 100 matched pairs of gallbladder cancer tissues. A positive correlation between high epidermal growth factor receptor expression levels and poor prognosis was observed in gallbladder cancer tissues. Pharmacological inhibition or inhibition via RNA interference of epidermal growth factor receptor induced cellular senescence in gallbladder cancer cells. The antitumor effect of arctigenin on gallbladder cancer cells was primarily achieved by inducing cellular senescence. In gallbladder cancer cells treated with arctigenin, the expression level of epidermal growth factor receptor significantly decreased. The analysis of the activity of the kinases downstream of epidermal growth factor receptor revealed that the RAF-MEK-ERK signaling pathway was significantly inhibited. Furthermore, the cellular senescence induced by arctigenin could be reverted by pcDNA-epidermal growth factor receptor. Arctigenin also potently inhibited the growth of tumor xenografts, which was accompanied by the downregulation of epidermal growth factor receptor and induction of senescence. This study demonstrates arctigenin could induce cellular senescence in gallbladder cancer through the modulation of epidermal growth factor receptor pathway. These data identify epidermal growth factor receptor as a key regulator in arctigenin-induced gallbladder cancer senescence.

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Biomolecular bases of the senescence process and cancer. A new approach to oncological treatment linked to ageing

Cited by 21 publications

References 212 publications

Ultraconserved region-containing Transformer 2β4 controls senescence of colon cancer cells

Ultraconserved region-containing Transformer 2β4 controls senescence of colon cancer cells

ROS, Cell Senescence, and Novel Molecular Mechanisms in Aging and Age‐Related Diseases

Arctigenin induced gallbladder cancer senescence through modulating epidermal growth factor receptor pathway

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