The implication of ROCK 2 as a potential senotherapeutic target via the suppression of the harmful effects of the SASP: Do senescent cancer cells really engulf the other cells?

Demir, Yaprak Dilber Şimay; Özdemir, Ayşegül; Sucularli, Ceren; Benhür, Elifnur; Ark, Mustafa

doi:10.1016/j.cellsig.2021.110007

Cited by 9 publications

(7 citation statements)

References 52 publications

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“…Recently, we proposed Rho kinase (ROCK) inhibition as a novel alternative for SASP regulation, as in in vitro experiments using senescent oral keratinocytes, Y-27632 (a commonly used ROCK inhibitor) was able to reduce the secreted levels of the signature SASP factors IL-1α, IL-1β, IL-6 and IL-8, without compromising the cell cycle arrest [ 129 ]. Similar results have been reported by others after [ 130 ].…”

Section: Targeting Senescent Cells In Cancersupporting

confidence: 93%

Senescent Cells in Cancer: Wanted or Unwanted Citizens

Niklander

Lambert

Hunter

2021

Cells

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Over recent decades, the field of cellular senescence has attracted considerable attention due to its association with aging, the development of age-related diseases and cancer. Senescent cells are unable to proliferate, as the pathways responsible for initiating the cell cycle are irreversibly inhibited. Nevertheless, senescent cells accumulate in tissues and develop a pro-inflammatory secretome, known as the senescence-associated secretory phenotype (SASP), which can have serious deleterious effects if not properly regulated. There is increasing evidence suggesting senescent cells contribute to different stages of carcinogenesis in different anatomical sites, mainly due to the paracrine effects of the SASP. Thus, a new therapeutic field, known as senotherapeutics, has developed. In this review, we aim to discuss the molecular mechanisms underlying the senescence response and its relationship with cancer development, focusing on the link between senescence-related inflammation and cancer. We will also discuss different approaches to target senescent cells that might be of use for cancer treatment.

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Section: Targeting Senescent Cells In Cancersupporting

confidence: 93%

Senescent Cells in Cancer: Wanted or Unwanted Citizens

Niklander

Lambert

Hunter

2021

Cells

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“…Although reduction of SASP component production is an aspect of traditional senomorphic treatment, the release process of SASP is rarely targeted for interference. Recently, it was reported that inhibition of Rho/Rho kinase with CT04 and Y27632 may not only alter the morphology of senescent cells but also affect the secretion of senescent cells via changes in the ER/Golgi system (Simay Demir et al, 2021). Alternatively, more direct inhibition can be achieved by specific neutralizing monoclonal antibodies against SASP factors, such as MABp1 for IL-1α, ABX-IL-8 for IL-8 and olokizumab for IL-6 (von Kobbe, 2019).…”

Section: Senomorphicsmentioning

confidence: 99%

Roles of extracellular vesicles in the aging microenvironment and age‐related diseases

Yin

Chen

Wang

et al. 2021

J of Extracellular Vesicle

103

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Cellular senescence is a persistently hypoproliferative state with diverse stressors in a specific aging microenvironment. Senescent cells have a double-edged sword effect: they can be physiologically beneficial for tissue repair, organ growth, and body homeostasis, and they can be pathologically harmful in age-related diseases. Among the hallmarks of senescence, the SASP, especially SASP-related extracellular vesicle (EV) signalling, plays the leading role in aging transmission via paracrine and endocrine mechanisms. EVs are successful in intercellular and interorgan communication in the aging microenvironment and age-related diseases. They have detrimental effects on downstream targets at the levels of immunity, inflammation, gene expression, and metabolism. Furthermore, EVs obtained from different donors are also promising materials and tools for antiaging treatments and are used for regeneration and rejuvenation in cell-free systems. Here, we describe the characteristics of cellular senescence and the aging microenvironment, concentrating on the production and function of EVs in age-related diseases, and provide new ideas for antiaging therapy with EVs.

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“…Many genes upregulated in the OR cell lines are important in cell cycle regulation ( Figure 3 d). Among these genes, ROCK2 plays an essential role in the G1/S phase transition, and studies have shown that its depletion or inhibition leads to both a cell cycle arrest and a senescent phenotype associated with a modification of the composition of the senescence-associated secretory phenotype (SASP) [ 23 , 47 ]. Olaparib is already known to induce a senescence-like phenotype in ovarian cancer cells, which can contribute to tumor progression and acquired PARPi resistance [ 48 , 49 ].…”

Section: Discussionmentioning

confidence: 99%

Development of Olaparib-Resistance Prostate Cancer Cell Lines to Identify Mechanisms Associated with Acquired Resistance

Cahuzac

Péant

Mes-Masson

et al. 2022

Cancers

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Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) were initially deployed to target breast and ovarian tumors with mutations in DNA damage response genes. Recently, PARPi have been shown to be beneficial in the treatment of prostate cancer (PC) patients having exhausted conventional therapeutics. Despite demonstrating promising response rates, all patients treated with PARPi eventually develop resistance. However, PARPi resistance in PC is not well understood, and further studies are required to understand PARPi resistance in PC to propose strategies to circumvent resistance. Methods: Starting from well-established olaparib-sensitive PC cell lines (LNCaP, C4-2B and DU145), we derived olaparib-resistant (OR) PC cell lines and performed a microarray analysis. Results: The olaparib IC50 values of OR cell lines increased significantly as compared to the parental cell lines. Gene expression analyses revealed that different pathways, including DNA repair, cell cycle regulation and autophagy, were affected by acquired resistance. A total of 195 and 87 genes were significantly upregulated and downregulated, respectively, in all three OR cell lines compared to their parental counterparts. Among these genes, we selected BRCC3, ROCK2 and ATG2B for validation. We showed that ROCK2 expression, basal autophagy and homologous recombination (HR) efficiency were increased in all OR cell lines. Conclusions: Our study provides a new in vitro model to study PARPi resistance in PC and suggests new possible targets to reverse resistance and prolong the benefits of PARPi treatment.

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The implication of ROCK 2 as a potential senotherapeutic target via the suppression of the harmful effects of the SASP: Do senescent cancer cells really engulf the other cells?

Cited by 9 publications

References 52 publications

Senescent Cells in Cancer: Wanted or Unwanted Citizens

Senescent Cells in Cancer: Wanted or Unwanted Citizens

Roles of extracellular vesicles in the aging microenvironment and age‐related diseases

Development of Olaparib-Resistance Prostate Cancer Cell Lines to Identify Mechanisms Associated with Acquired Resistance

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