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Review
. 2022 Sep 21;23(19):11082.
doi: 10.3390/ijms231911082.

Senescence of Tumor Cells in Anticancer Therapy-Beneficial and Detrimental Effects

Wiktoria Monika Piskorz  1 , Marzanna Cechowska-Pasko  1
Affiliations
Review

Senescence of Tumor Cells in Anticancer Therapy-Beneficial and Detrimental Effects

Wiktoria Monika Piskorz et al. Int J Mol Sci. .

Abstract

Cellular senescence process results in stable cell cycle arrest, which prevents cell proliferation. It can be induced by a variety of stimuli including metabolic stress, DNA damage, telomeres shortening, and oncogenes activation. Senescence is generally considered as a process of tumor suppression, both by preventing cancer cells proliferation and inhibiting cancer progression. It can also be a key effector mechanism for many types of anticancer therapies such as chemotherapy and radiotherapy, both directly and through bioactive molecules released by senescent cells that can stimulate an immune response. Senescence is characterized by a senescence-associated secretory phenotype (SASP) that can have both beneficial and detrimental impact on cancer progression. Despite the negatives, attempts are still being made to use senescence to fight cancer, especially when it comes to senolytics. There is a possibility that a combination of prosenescence therapy-which targets tumor cells and causes their senescence-with senotherapy-which targets senescent cells, can be promising in cancer treatment. This review provides information on cellular senescence, its connection with carcinogenesis and therapeutic possibilities linked to this process.

Keywords: SASP; cancer; prosenescence therapy; senescence; senolysis; senolytics; senostatics; therapy.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Retinoblastoma (RB)-dependent cell cycle arrest. In normal cells RB is phosphorylated by cyclin-dependent kinases (CDKs). Enhancement of E2F transcription factor activity occurs, which is required for cell cycle progression. In senescent cells, CDKs are inhibited by P16 or P21, which can be activated as a result of DNA damage response (DDR) through ataxia telangiectasia and Rad3-related kinase (ATR)/ataxia telangiectasia mutated kinase (ATM) → checkpoint kinase 1 /checkpoint kinase 2 (CKH1/CHK2) → P53 pathway. E2F repression occurs, which leads to the cell cycle arrest maintained by the senescence-associated secretory phenotype (SASP) and reactive oxygen species (ROS).
Figure 3
Figure 3
Manipulating senescence in order to eliminate tumor cells by senolysis. Inhibitors of telomerase (such as imetelstat), inhibitors of topoisomerase (i.e., doxorubicin), cyclin-dependent kinases (CDKs) inhibitors (like ribociclib), oxidative stress inducers (such as CopA3) as well as P53 protein modulators (i.e., dasatinib) (orange arrows) may promote tumor cells senescence. Subsequently, via using mammalian target of rapamycin (mTOR) inhibitors (such as temsirolimus), B-cell lymphoma 2 (BCL-2) inhibitors (like navitoclax), Na+/K+ pump inhibitors (such as digoxine) or P53 modulators (like FOXO4-DRI), senolysis of senescent cancer cells can be induced.
Figure 2
Figure 2
Positive (green arrows) and negative (red arrows) effects of senescence on cancer progression. Growth factors and metalloproteinases (MMP), released by senescent cells, as well as epithelial-to-mesenchymal transformation (EMT) lead to the cancer vascularization. MMPs also support cancer migration. Other (SASP) components, such as interleukin 1 α (IL-1 α), interleukin 6 (IL-6), interleukin 8 (IL-8) result in inflammation, which promotes cancer progression. On the other hand, senescence has also a preventive activity. Some of the SASP components, such as IL-6, IL-8, plasminogen activator inhibitor (PAI-1), insulin-like growth factor-binding protein 7 (IGFBP7) support cell cycle arrest and prevent cancer progression. Moreover, due to the senescence, immune cells recruitment and changes in macrophage polarity occur that prevent cancer progression.
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This research received no external funding.

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