Therapy-Induced Senescence (TIS) and SASP: The p53-Mediated Interplay in Cancer Progression and Treatment
Chang Hoon Lee1, Tuan Minh Nguyen1, Yongook Lee1
1BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University, Goyang 10326, Republic of Korea.
Abstract:
Cellular senescence, initially regarded as a potent tumor-suppressive mechanism, is now recognized as a double-edged sword that modulates the hallmarks of cancer. The tumor suppressor p53 typically orchestrates this process to inhibit tumorigenesis; however, mutations in p53 or its regulators can subvert this program, leading to senescence evasion and therapy resistance. In particular, therapy-induced senescence can paradoxically drive tumor progression via the senescence-associated secretory phenotype, which creates a pro-tumorigenic microenvironment dictated by p53-mediated regulation of NF-κB signaling. Here, we explore the p53-mediated senescence-cancer interplay and evaluate emerging therapies, including senolytics and immunotherapies. We propose that strategic modulation of senescence offers a promising paradigm for future anticancer therapy.
Insights
Cellular senescence, a process involving cell cycle arrest, has a dual role in cancer. While it can suppress tumors, it can also promote cancer growth through the senescence-associated secretory phenotype, especially when p53 is mutated.
Area of Science:
- Oncology
- Cell Biology
- Molecular Biology
Background:
- Cellular senescence is a complex biological process with implications in cancer.
- Initially viewed as a tumor-suppressive mechanism, its role is now understood to be multifaceted.
- The tumor suppressor p53 plays a key role in orchestrating senescence and inhibiting tumorigenesis.
Purpose of the Study:
- To explore the intricate relationship between p53-mediated cellular senescence and cancer.
- To investigate how senescence evasion and therapy resistance occur due to p53 mutations.
- To evaluate emerging therapeutic strategies targeting senescence in cancer treatment.
Main Methods:
- Review of existing literature on cellular senescence and cancer.
- Analysis of p53's role in regulating senescence and its impact on tumor microenvironment.
- Examination of the senescence-associated secretory phenotype (SASP) and NF-κB signaling pathways.
- Evaluation of senolytics and immunotherapies as potential cancer treatments.
Main Results:
- Mutations in p53 can lead to senescence evasion and therapy resistance.
- Therapy-induced senescence can paradoxically promote tumor progression via SASP.
- p53-mediated regulation of NF-κB signaling is crucial in creating a pro-tumorigenic microenvironment.
- Senescence acts as a double-edged sword, modulating cancer hallmarks.
Conclusions:
- Strategic modulation of cellular senescence presents a promising therapeutic avenue for cancer.
- Targeting senescence, particularly through senolytics and immunotherapies, holds potential for future anticancer strategies.
- Understanding the p53-mediated senescence-cancer interplay is critical for developing effective cancer therapies.
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