Cellular senescence in cancer: molecular mechanisms and therapeutic targets

MedComm, Journal Year: 2024, Volume and Issue: 5(5)

Published: April 24, 2024

Abstract Aging exhibits several hallmarks in common with cancer, such as cellular senescence, dysbiosis, inflammation, genomic instability, and epigenetic changes. In recent decades, research into the role of senescence on tumor progression has received widespread attention. While how limits course cancer is well established, also been found to promote certain malignant phenotypes. The tumor‐promoting effect mainly elicited by a senescence‐associated secretory phenotype, which facilitates interaction senescent cells their surroundings. Targeting therefore offers promising technique for therapy. Drugs that pharmacologically restore normal function or eliminate them would assist reestablishing homeostasis cell signaling. Here, we describe its occurrence, impact biology. A “one‐two‐punch” therapeutic strategy first induced, followed use senotherapeutics eliminating introduced. advances application targeting treatment are outlined, an emphasis drug categories, strategies screening, design, efficient targeting. This work will foster thorough comprehension encourage additional within this field.

Language: Английский

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ARv7 promotes the escape of prostate cancer cells from androgen deprivation therapy-induced senescence by mediating the SKP2/p27 axis

BMC Biology, Journal Year: 2025, Volume and Issue: 23(1)

Published: Feb. 28, 2025

Androgen deprivation therapy (ADT) induces cellular senescence and tumor stasis, thus serving as the standard treatment for prostate cancer (PCa). However, continuous suppression of canonical androgen receptor signaling actually leads to switch from androgen-responsive growth androgen-independent growth, contributing "escape" this ADT-induced (AIS) and, subsequently, development castration-resistant (CRPC). Unfortunately, mechanism underlying phenomenon remains elusive. In study, we demonstrated that splicing variant 7 (ARv7), a dominant factor mediating abnormal AR ADT resistance, is closely associated with outgrowth AIS PCa cells. Mechanistically, ARv7 binds promoter SKP2, activating its transcription, then promotes proteasomal degradation cell cycle regulator p27 G1/S transition. addition, applied bioinformatic in vitro analyses show SKP2 expression level dramatically inhibited upon ADT, but reactivation one key step during establishment CRPC. Finally, also inhibitor can significantly inhibit lines enhance efficacy ADT. Our work reveals novel role regulating suggests targeting ARv7/SKP2/p27 axis could be potential strategy delay disease progression CRPC state prolonged

Language: Английский

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Single-cell omics traces the heterogeneity of prostate cancer cells and the tumor microenvironment

Cellular & Molecular Biology Letters, Journal Year: 2023, Volume and Issue: 28(1)

Published: May 9, 2023

Abstract Prostate cancer is one of the more heterogeneous tumour types. In recent years, with rapid development single-cell sequencing and spatial transcriptome technologies, researchers have gained a intuitive comprehensive understanding heterogeneity prostate cancer. Tumour-associated epithelial cells; cancer-associated fibroblasts; complexity immune microenvironment, distribution cells other cancer-promoting molecules play crucial role in growth, invasion, metastasis Single-cell multi-omics biotechnology, especially sequencing, reveals expression level single higher resolution finely dissects molecular characteristics different cells. We reviewed literature on cells, focusing RNA sequencing. And we analysed differences cell discussed impact novel omics such as rich exploration strategies, joint analysis modes, deep learning models, future research. this review, constructed catalogue studies This article aimed to provide thorough diagnosis treatment summarised proposed several key issues directions applying transcriptomics understand Finally, trends

Language: Английский

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The protein composition of exosomes released by prostate cancer cells is distinctly regulated by androgen receptor-antagonists and -agonist to stimulate growth of target cells

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: April 8, 2024

Abstract Background Prostate cancer (PCa) is a prevalent malignancy in men worldwide, ranking as the second leading cause of cancer-related death Western countries. Various PCa hormone therapies, such androgen receptor (AR)-antagonists or supraphysiological level (SAL) reduce cell proliferation. However, treated cells may influence growth neighboring through secreted exosomes tumor microenvironment (TME). Here, change protein content from treatment with different AR-antagonists SAL has been analyzed. Methods Isolation via ultracentrifugation human LNCaP AR-agonist and various AR-antagonists; analysis cellular senescence by detection associated beta galactosidase activity (SA β-Gal); blotting immunofluorescence staining; Mass spectrometry (MS-spec) bioinformatic analyses to identify ligand-specific exosomal proteins. Growth assays analyze on non-treated cells. Results MS-spec identified proteins exosomes. One thousand seventy were up- 52 downregulated whereas enzalutamide upregulated 151 42 The prediction indicates an up-regulation pro-proliferative pathways. AR ligands augment hub factors that include AKT1, CALM1, PAK2 CTNND1. Accordingly, functional confirmed isolated AR-ligand promote untreated Conclusion data suggest cargo controlled -antagonists distinct among AR-antagonists. Further, might TME. This finding sheds light into complex interplay between signaling exosome-mediated communication

Language: Английский

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

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: April 17, 2024

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

Language: Английский

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Cellular Aging and Senescence in Cancer: A Holistic Review of Cellular Fate Determinants

Aging and Disease, Journal Year: 2024, Volume and Issue: unknown, P. 0 - 0

Published: Jan. 1, 2024

This comprehensive review navigates the complex relationship between cellular aging, senescence, and cancer, unraveling determinants of fate. Beginning with an overview aging's significance in explores processes, changes, molecular pathways influencing senescence. The senescence as a dual mechanism acting suppressor contributor, focusing on its impact therapy response. highlights opportunities for cancer therapies that target further examines senescence-associated secretory phenotype strategies to modulate aging influence tumor behavior. Additionally, mechanisms escape cells, emphasizing their prognosis resistance therapy. article addresses current advances, unexplored aspects, future perspectives understanding cancer.

Language: Английский

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The clock gene BHLHE40 and atypical CCNG2 control androgen-induced cellular senescence as a novel tumor suppressive pathway in prostate cancer

Journal of Experimental & Clinical Cancer Research, Journal Year: 2024, Volume and Issue: 43(1)

Published: June 20, 2024

Abstract Background The androgen receptor (AR) is a drug target used to inhibit AR and prostate cancer (PCa) growth. Surprisingly, treatment with supraphysiological level (SAL), in bipolar therapy, inhibits growth of PCa suggesting tumor-suppressive activity by SAL. SAL was shown induce cellular senescence PCa. Methods RNA-seq transcriptome analysis, ChIP-seq, human 3D spheroids, mouse xenografted castration-resistant PCa, knockdown overexpression, Co-immunoprecipitation (Co-IP), translocation immune detection, qRT-PCR, protein–protein interaction modelling. Results Here, mice xenografts tumors show that vivo activates mechanism. ChIP-seq revealed the clock gene BHLHE40 novel direct target. Compared adjacent tissues, expression reduced associated survival. Knockdown suggests mediates SAL-induced including tumor spheroids. Interestingly, large overlap differentially expressed sets identified between leading identification four classes SAL-BHLHE40 landscapes. Co-IP modelling suggest binding their co-translocation into nucleus treatment. Further, analysis indicate atypical suppressive cyclin G2 emerged as downstream mediator senescence. Conclusions data provide evidence signaling AR-BHLHE40-CCNG2 axis for androgen-induced senescence, linking circadian rhythm factor pathway.

Language: Английский

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The interplay of p16INK4a and non-coding RNAs: bridging cellular senescence, aging, and cancer

Biogerontology, Journal Year: 2025, Volume and Issue: 26(2)

Published: Feb. 5, 2025

Language: Английский

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Spatio-temporal model of combining ADT and chemotherapy with senolytic treatment in metastatic prostate cancer

Journal of Theoretical Biology, Journal Year: 2025, Volume and Issue: 602-603, P. 112069 - 112069

Published: Feb. 18, 2025

Language: Английский

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Mechanism of Action and Interaction of Garlic Extract and Established Therapeutics in Prostate Cancer

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(4), P. 1777 - 1777

Published: Feb. 19, 2025

A detailed characterization of the mechanism action garlic extract (GE) on prostate cancer (PCa) cells is essential to ensure its safe use as a complementary therapy, particularly when combined with established treatments. case report highlighted potential benefits GE in PCa management. patient diagnosed PCa, presenting an initial prostate-specific antigen (PSA) 11.8 ng/mL, maintained PSA levels between 3.5 and 6 ng/mL for over 14 years daily intake. To study GE's anti-proliferative effects interactions therapeutics, healthy epithelial (PNT2) (LNCaP, PC3, VCaP) were treated GE. Proliferation, Integrin β1 pattern, DNA-damage, well androgen receptor (AR) Cytochrome P450 (CYP450) expression investigated. reduced proliferation LNCaP PC3 compared PNT2 but had contrary VCaP cells. The combination standard therapies, including chemotherapy, deprivation therapy (ADT), Poly-(ADP-ribose)-Polymerase inhibitors (PARPi), efficacy these treatments tumor cells, potentially due GE-induced upregulation metabolic enzyme CYP2C9 cell lines. These findings indicate that while has effects, highly concentrated natural extracts must be carefully assessed by expert physicians case-by-case basis, especially therapies.

Language: Английский

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