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Review
. 2024 Sep;30(3):162.
doi: 10.3892/mmr.2024.13286. Epub 2024 Jul 12.

Cellular senescence in metastatic prostate cancer: A therapeutic opportunity or challenge (Review)

Cen Jin #  1 , Sijian Liao #  2 , Guoliang Lu  3 , Bill D Geng  4 , Zi Ye  2 , Jianwei Xu  1 , Guo Ge  5 , Dan Yang  6
Affiliations
Review

Cellular senescence in metastatic prostate cancer: A therapeutic opportunity or challenge (Review)

Cen Jin et al. Mol Med Rep. 2024 Sep.

Abstract

The treatment of patients with metastatic prostate cancer (PCa) is considered to be a long‑standing challenge. Conventional treatments for metastatic PCa, such as radical prostatectomy, radiotherapy and androgen receptor‑targeted therapy, induce senescence of PCa cells to a certain extent. While senescent cells can impede tumor growth through the restriction of cell proliferation and increasing immune clearance, the senescent microenvironment may concurrently stimulate the secretion of a senescence‑associated secretory phenotype and diminish immune cell function, which promotes PCa recurrence and metastasis. Resistance to established therapies is the primary obstacle in treating metastatic PCa as it can lead to progression towards an incurable state of disease. Therefore, understanding the molecular mechanisms that underly the progression of PCa is crucial for the development of novel therapeutic approaches. The present study reviews the phenomenon of treatment‑induced senescence in PCa, the dual role of senescence in PCa treatments and the mechanisms through which senescence promotes PCa metastasis. Furthermore, the present review discusses potential therapeutic strategies to target the aforementioned processes with the aim of providing insights into the evolving therapeutic landscape for the treatment of metastatic PCa.

Keywords: metastasis; prostate cancer; secretome; senescence; therapy.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1.
Figure 1.
Characterization of cellular senescence. Cellular senescence can be triggered by various stimuli, such as oxidative stress, oncogene activation, and DNA or telomere damage. The p53, p21 and p16 pathways are the primary pathways that induce senescence in cancerous tissues. Senescent cells exhibit irreversible cell cycle arrest. Concurrently, senescent cells secrete a number of factors, including proinflammatory cytokines and chemokines, growth regulators, angiogenic factors and matrix metalloproteinases, which are collectively referred to as the SASP. Senescence can be amplified through either an autocrine or a paracrine mechanism that releases SASP factors to promote senescence in adjacent tumor cells. SASP, senescence-associated secretory phenotype.
Figure 2.
Figure 2.
Mechanisms of SASP generation. The SASP is regulated at the epigenetic, transcriptional and post-transcriptional levels in senescent cells. Regulation of the SASP is governed by a number of transcription factors, with NF-κB serving a key role in this response. The cytoplasmic DNA damage response is associated with senescence activation and SASP expression. NOTCH1 signaling modulates the secretome of senescent cells through inhibition of C/EBPβ, which suppresses the secretion of proinflammatory factors and impedes the recruitment of immune cells to the tumor site. The binding of IL-1α to IL-1R1 promotes the recruitment of IRAK1, which activates downstream factors and reactivates NF-κB. DSB, double strand break; IRAK, IL-1 receptor associated kinase; STING, stimulator of IFN genes; MK2, MAPK-activated protein kinase 2; SASP, senescence-associated secretory phenotype; IL-1R1, IL-1 receptor 1; GATA4, GATA-binding protein 4; N1ICD, NOTCH1 intracellular domain; MAML, mastermind-like protein 1; CCL20, chemokine (C-C motif) ligand 20; C/EBPβ, CCAAT/enhancer-binding protein β.
Figure 3.
Figure 3.
Use of senolytic and senomorphic therapies to improve cancer treatment. Conventional cancer treatments, such as chemotherapy, radiotherapy and targeted therapy, induce treatment-induced senescence. The strategic approach of selectively eliminating senescent cells using senolytic therapy, or inhibiting the production and secretion of the SASP by senescent cells using senomorphic therapy may be an effective strategy for addressing PCa metastasis. PCa, prostate cancer; SASP, senescence-associated secretory phenotype; ATM, ataxia telangiectasia mutated; ADT, androgen deprivation therapy; HSP90, heat shock protein 90; DPP4, dipeptidyl peptidase 4.
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Grants and funding

The present review was supported by the College Students' Innovation and Entrepreneurship Training Program (grant no. S202210660072) and the Undergraduate Teaching Research Project of Guizhou Medical University (grant no. JG2023046). Partial support was provided by the Natural Science Foundation Project of Guizhou Provincial Science and Technology Department (grant no. Qiankehe Foundation-ZK 2024 General 182).