A new perspective on prostate cancer treatment: the interplay between cellular senescence and treatment resistance

Abstract

The emergence of resistance to prostate cancer (PCa) treatment, particularly to androgen deprivation therapy (ADT), has posed a significant challenge in the field of PCa management. Among the therapeutic options for PCa, radiotherapy, chemotherapy, and hormone therapy are commonly used modalities. However, these therapeutic approaches, while inducing apoptosis in tumor cells, may also trigger stress-induced premature senescence (SIPS). Cellular senescence, an entropy-driven transition from an ordered to a disordered state, ultimately leading to cell growth arrest, exhibits a dual role in PCa treatment. On one hand, senescent tumor cells may withdraw from the cell cycle, thereby reducing tumor growth rate and exerting a positive effect on treatment. On the other hand, senescent tumor cells may secrete a plethora of cytokines, growth factors and proteases that can affect neighboring tumor cells, thereby exerting a negative impact on treatment. This review explores how radiotherapy, chemotherapy, and hormone therapy trigger SIPS and the nuanced impact of senescent tumor cells on PCa treatment. Additionally, we aim to identify novel therapeutic strategies to overcome resistance in PCa treatment, thereby enhancing patient outcomes.

Keywords: SIPS; cellular senescence; drug resistance; prostate cancer; treatment resistance.

Figure 1

Molecular pathways of therapies-induced senescence in PCa. Radiotherapy and chemotherapy lead to irreversible DNA damage, ultimately triggering the activation of p53 and p21. p21 inhibits CDKs and mediates senescence by preventing the phosphorylation of Rb. In addition, chemotherapy induces senescence through ROS-ETS-p16 pathway. Androgen deprivation therapy induce senescence through Skp2-p27 pathway (created in Biorender.com).

Figure 2

The dual effects of senescent cells in PCa. Therapy-induced senescent cancer cells secrete production of IL-6, IL-8, LCN2 and other senescence-associated secretory phenotype (SASP) factors. These factors exert juxtacrine and paracrine effects on the surrounding tumor microenvironment thereby anti-tumor or treatment resistance (created in Biorender.com). EMT, Epithelial-to-mesenchymal transition; VEGF, Vascular endothelial growth factor; LCN2, lipocalin 2.

Figure 3

Summary diagram for therapies-induced senescence and dual effects in PCa. SASP, senescence-associated secretory phenotype; EMT, Epithelial-to-mesenchymal transition; VEGF, Vascular endothelial growth factor; LCN2, lipocalin 2.